Perspective

Special Focus: Cardiovascular Diseases

For reprint orders, please contact [email protected]

Antidiabetic agents: past, present and future

Treatment of diabetes mellitus requires, at a certain stage of its course, drug intervention. This article reviews the
properties of available antidiabetic medications and highlights potential targets for developing newer and safer
drugs. Antidiabetic agents are grouped in the article as parts I, II and III according to the history of development.
Part I groups early developed drugs, during the 20th century, including insulin, sulfonylureas, the metiglinides, insulin
sensitizers, biguanides and a-glucosidase inhibitors. Part II groups newer drugs developed during the early part of
the 21st century, the past decade, including GLP-1 analogs, DPP-VI inhibitors, amylin analogs and SGLT2 inhibitors.
Part III groups potential targets for future design of newer antidiabetic agents with less adverse effects than the
currently available antidiabetic drugs.

Diabetes mellitus as an epidemic glucose levels after the oral glucose tolerance Ahmed Mehanna
disease test. In search of more accurate diagnostic tests, Department of Pharmaceutical
Diabetes mellitus is a disease state characterized experts on diabetes diagnosis recommended Sciences School of Pharmacy, Boston
MCPHS University (Formerly
by defect in the ability of cells to utilize glucose in 2009 the use of glycosylated hemoglobin Massachusetts College of Pharmacy &
for vital biological processes. The underlying (HbA1c), with a threshold of 6.5% or above, as Health Sciences) 179 Longwood
Avenue, Boston, MA 02115, USA
pharmacological basis for the disease relates to the criteria for diabetes diagnosis. In 2010, The Tel.: +1 617 732 2955
either deficiency in circulating insulin resulting American Diabetes Association (ADA) adapted Fax: +1 617 732 2228
from progressive destruction of the pancreatic the recommendations to use HbA1c as a crite- E-mail: [email protected]

beta cells as the case is with Type 1 diabetes; or rion for diagnosis and for therapy evaluation [1] .
to an inadequate release of insulin from the beta HbA1c number is an indication of the degree of
cells as the case is with Type 2 diabetes. A more modification of hemoglobin A, resulting from
complex state of diabetes commonly described covalent interaction of plasma glucose with the
as insulin resistant diabetes in which insulin terminal amino group of hemoglobin A chain.
may be circulating in sufficient amounts but its The ADA recommends measurement of HbA1c
receptors become insensitive. Insulin receptor at least twice a year.
stimulation is essential to facilitate glucose entry
into almost every living cell, with the exception Classification of diabetes mellitus
of brain cells, to produce the necessary energy According to the ADA, there are four known
for various cell functions. Diabetes mellitus is clinical types of diabetes mellitus: Type 1,
a worldwide health problem declared by the Type 2, special types and gestational diabetes.
WHO as an epidemic disease to be the only While Type 1 is associated with the destruction
noninfectious disease with such categorization. of the pancreatic beta cells that produce insulin,
An estimated 347 million people worldwide are Type 2 is associated with progressive defect in
reported to have diabetes mellitus. Available insulin secretion with potential development of
data indicate that 3.4 million died in 2004 alone insulin resistance. The special types of diabetes
from consequences of diabetes with a projection are those resulting from exposure to chemicals,
that number will increase by two-thirds by the immunosuppressive drugs and other diseases.
year 2030 [301] . At the national level, data from The gestational diabetes develops with preg-
the National Diabetes Fact Sheet in the USA, nancy. The present review addresses available
released in 2011, indicate that 25.8 million drugs and compounds in preclinical trials to
children and adults (8.3% of the population) treat Type 1 and Type 2 diabetes.
have diabetes and 79 million people are living
as pre-diabetics [302] . Diabetes & cardiovascular
complications
Laboratory test for diabetes diagnosis: Although diabetes mellitus has an original
HbA1c etiology of endocrine nature, the disease has
For decades, the primary tool for diabetes diag- damaging effects on several cellular, tissue and,
nosis was the measurement of fasting blood ultimately, organ functions. However, most

10.4155/FMC.13.13 © 2013 Future Science Ltd Future Med. Chem. (2013) 5(4), 411–430 ISSN 1756-8919 411
Perspective | Mehanna
morbidity and mortality incidences associated physical activity on controlling Type 1 diabetes
with the disease attributed mainly to its detri- has been reported recently [21,201] . Several other
mental cardiovascular complications. Scores of new reports addressed the effects of diet and
research articles and reviews have appeared in physical activity on blood pressure and glucose
the literature emphasizing the effects of diabetes concentrations in Type 2 diabetic patients [22–24] .
on the cardiovascular system [2–9] . In addition The ADA recommends initiating drug ther-
to the development of hypertension and imbal- apy as a second step, after diet and exercise,
ance in lipid metabolism as common complica- to control diabetes. Recommended drugs for
tions for diabetes, a close correlation established treatment differ for Type 1 from that for Type 2.
linking the cardiovascular complications to the
observed disturbances in the cellular oxidative Insulin & Type 1 diabetes mellitus
stress and the red blood cell oxidation–reduction As defined by the ADA, Type 1 diabetes is asso-
system [6,10–15] . Blood vessel epithelium becomes ciated with progressive destruction of the beta
dysfunctional as a major complication for dia- cells of the pancreas. Administration of exter-
betes [16] . A study has associated diabetes with nal insulin is the most common therapy to treat
increased expression of the angiotensin convert- Type 1 diabetes. A new agent, Pramlinitide,
ing enzyme as over active polymorphic forms, recently approved by the US FDA for the treat-
by gene insertion and deletion, leading to ment of Type 1 diabetes as discussed under
increased hypertension and renal nephropathy part II of this article. Insulin-based therapy is
as complications [17,18] . associated with several drawbacks including the
requirement of multiple injections and potential
Treatment of diabetes mellitus development of hypoglycemia if the dose is not
In general, management of diabetes mellitus and properly adjusted.
prevention of its complications achieved through
either diet control and physical exercise or use Type 2 diabetes & antidiabetic drugs:
of antidiabetic drugs or combination of both. an overview
As defined by the ADA, Type 2 diabetes results
Diet & physical activity from a progressive defect in insulin secretion
The guidelines of the ADA recommend that from the beta cells on the background of insulin
a healthy and balanced diet, regular physical resistance. Several drug classes are available to
activity, maintaining a normal body weight and manage Type 2 diabetes including sulfonylurea
avoiding tobacco use can prevent or delay the secretagogues, non-sulfonylurea secretagogues,
onset of diabetes complications [19] . A healthy biguanides, insulin sensitizers (the thiazolidin-
diet may be composed of 25–30 g of fiber per diones) and the a-glucosidase inhibitors. The
day, with special emphasis on soluble fiber above listed drug classes constitute the backbone
sources (7–13 g). Protein daily intake should of standard, or traditional, drug therapy for
be 15–20% of the daily energy need. Alcohol Type 2 diabetes. Several newer drugs developed
consumption should be limited to one drink in the last decade for treatment of Type 2 dia-
per day for women and two drinks per day for betes including GLP-1 analogs, DPP-IV inhibi-
men. Carbohydrates from fruits, vegetables, tors, amylin analogs, and, most recently in 2012,
whole grains, legumes and low-fat milk should SGLT inhibitors.
be encouraged. Dietary fat and cholesterol can
be provided by two or more servings of fish per Efficacy versus adverse effects of the
week (with the exception of commercially fried antidiabetic drugs
fish filets) to provide n-3 polyunsaturated fatty Each class of the above listed medications, control
acids, which were noted by the ADA to have ben- blood glucose level of Type 2 diabetes through a
eficial effects on the lipid profile. The guidelines distinct mechanism. The ADA recommends the
recommend 90–150 min/week of physical activ- use of combination regimens for Type 2 diabetes
ity to improve the control on blood sugar level treatment to integrate one or more of such mech-
[303] . A study on the relationship between healthy anisms. Unfortunately, standard antidiabetic
diet and the risk of cardiovascular complications agents are also associated with several unwanted
for patients from 40 countries has been recently adverse effects mostly cardiovascular in nature.
published [20] . The role of appetite suppressants A recent report by Ovalle examined how the
in reducing obesity and cardiovascular com- antidiabetic medications implemented in the
plications of diabetes and the importance of development of cardiovascular risk factors such

412 Future Med. Chem. (2013) 5(4) future science group

 Antidiabetic agents: past, present & future | Perspective
as body weight gain, blood pressure, and lipid periodical measurements of HbA1c level (at
profile [25] . The author concluded that that the least twice a year). If necessary, a combina-
antidiabetic medications have variable effects on tion of metformin and medications belong-
the development of cardiovascular risk factors and ing to other antidiabetic classes may be used.
recommends careful considerations in composing Recently, the ADA guidelines were modified,
regimens for diabetes Type 2 therapy. The FDA leaning towards recommending combination
current regulations mandate the availability of drug therapy rather than a single one. The ADA
clinical trials data assessing the safety and cardio­ also recommends self-monitoring by patients
vascular implications of any new antidiabetic for the efficacy of the administered drugs. Self
drug before approval for clinical use [26] . monitoring proven to result in an improvement
in HbA1c levels [31] .
The need for newer, safer antidiabetic This article is composed of three parts: I, II
drugs and III. Part I reviews earlier generation anti-
The cardiovascular adverse effects of the earlier diabetic drugs, developed during the 20th cen-
antidiabetic agents (developed during the 20th tury (the past), part II reviews drugs developed
century, the traditional ones) reported by Ovalle during the first decade of the 21st century (the
[25] , clearly indicate the need of newer drugs present) and part III reviews potential targets for
with better margin of safety. The advancement future drug design of newer antidiabetic agents
in biotechnology and the growing knowledge (the future).
and information about diabetes mellitus bio-
chemical and pharmacological bases; played a Part I: the past (early generation
significant role in developing newer antidiabetic antidiabetic agents)
agents [27,28] . The first decade of this century wit- As previously stated, insulin is the only available
nessed the development of several novel classes therapeutic option for the treatment of Type 1
of antidiabetic drugs that work by different diabetes. On the other hand, up and until
mechanisms than those of the early-developed approximately the middle of the past decade,
medications, with its long-term safety still under Type 2 diabetes treatment was limited to the
assessment. use of secretagogues (sulfonyureas and non-sul-
fonylureas), biguanides, the thiazolidin­diones
Guidelines for diabetes mellitus and the a-glucosidase inhibitors. In 2005, a
treatment detailed description of the chemical features,
The primary goal of all therapeutic approaches kinetic properties, trade names and mechanism
to treat diabetes is to control blood sugar level of action of insulin and the earlier generation
to prevent prolonged hyperglycemia, hence, antidiabetic drug classes were reported [32] . Since
reduce the risk of cardiovascular complications. the current review aims to be a comprehensive
Type 1 diabetes, with the beta cell destruction document for all available antidiabetic drugs, old
status, leaves insulin administration, three or and new, a summary for the 2005 article will be
more injections per day, or by use of insulin provided here in an abstract format.
pump, as the only available option for treat-
ment. For Type 2 diabetes, experts on diabetes Insulin
recommend the adherence to a healthy diet and „„Chemistry & biosynthesis
physical exercise as the first line of therapy. If Insulin is a polypeptide hormone of approxi-
diet and exercise fail to control the blood sugar mately 6000 molecular weight, composed of
level, drug therapy is then considered. Several two chains, A and B, connected through two
drug classes are available for clinical use to con- disulfide bridges. The hormone is biosynthesized
trol Type 2 diabetes, each with its advantages in the pancreatic beta cells as a single peptide
and disadvantages. Standards of medical care chain called ‘proinsulin’ with the A and B chains
for Type 2 diabetes are constantly updated by connected through a third chain ‘C’. Cleavage
the American Association of Diabetes of the of the connecting chain, ‘C’, provides the active
USA [29,30] , and the National Collaborative form of the hormone (Figure 1) .
Centre for Chronic Disease in the UK [301] .
The current guidelines recommend that man- „„Insulin function
agement for newly diagnosed Type 2 patients Insulin is a vital, if not the most vital, hormone
must start with diet and exercise, followed by for the biological system. With exception of
administering metformin (a biguanide) with brain cells, insulin facilitates glucose entry into

future science group www.future-science.com 413

Perspective | Mehanna
COOH 18–24 h duration of action. Premixed insulin
NH2
Residue 21 Asn
preparations containing different percentage of
Gly Residue 1 Chain A fast and long acting products, such as Humu-
Cys
ILe COOH lin® and Novolin® 10/90 are commercially
NH2 S Tyr
S Asn
available. The most unwanted adverse effects of
Val Residue
Thr insulin therapy for insulin-dependent Type 1
Phe Glu Glu 30
Gln Leu Lys patients, is the high risk of hypoglycemia if over-
Val Cys Gln S
Residue Cys Tyr Pro dose is administered. The repeated injections
Thr Ser Leu
Asn 1 ILe Cys Ser may become a potential source of infections
Thr
Gln S S and poses risk of local vascular complications.
Tyr
His Phe An insulin inhalation product (Exudra®) was
S
Leu Phe developed and evaluated as an alternative route
Cys Gly
Arg of insulin administration [33] with no further
Gly Glu reports on how successful it was or on how much
Ser
Gly
His
Cys
it contributed to correct the concern.
Leu
Val Glu Val
Ala Leu Tyr Leu
„„Insulin place in diabetes therapy
Chain B The importance of insulin in diabetes mellitus
therapy stems from that fact that it is the only
Figure 1. Active form of human insulin after cleavage of the connecting available agent to treat Type 1 diabetes. In addi-
chain. tion, insulin is also the last resort to manage
Type 2 diabetes in cases when oral antidiabetic
every living cell for energy production and vital agents fail to properly control blood glucose levels.
cellular activities. Insulin binding to its cellular Although insulin therapy leads to better outcomes
receptors activates an intrinsic protein kinase, on microcirculation, high incidences of hypo­
which, in turn, phosphorylates the cell mem- glycemic episodes occur with intensive regular
brane and increases its permeability to glucose insulin therapy. The newly developed rapid-act-
through a complex series of events. ing and long-acting insulin products were found
equally efficient in lower HbA1c, but with much
„„Regular human insulin & bio-engineered less incidences of hypoglycemic episodes [29] .
products
Regular human insulin has a 30 min onset and „„Summary of commercially available insulin
approximately 6–8 h duration of action. The products covered in Part I
slow onset of action of 30 min is problematic n Fast acting: Regular (Humulin R® ), lispro

in life-threatening conditions of hyperglycemia (Humalog®, Lispro-PFC®), aspart (Novolog®,

and the short duration of action, 6–8 h, requires Flexpen®), glulisine (Apidra®);
multiple daily injections. Lispro, aspart and glu-
lisine are analogs of human insulin produced n Intermediate acting: Isophane or NPH
using recombinant DNA technology through (Humulin N, Novolin N , Humulin PenN),
site-directed amino acid replacement, were lente (Humulin L, Novolin Ge Lente);
introduced to the market as the fast acting insu- n Long acting: Extended insulin suspension
lin products with onset of action of 10–15 min. (Humulin U, Novolin Ge), ultralente
These products are fast acting because the (Ultralente ®), glargine (Lantus®), detemir
chemically engineering process results in drugs (Levemir®);
with stabilized insulin–zinc monomer, the active
form of insulin. On the other hand, short dura- n Combination products of fast and long acting:
tion of action was resolved by preparing insulin Humulin 10/90, Novolin 10/90.
in suspension forms to reduce its dissolution at
the injection site. Lente, ultralente and NPH Drugs for the treatment of Type 2
insulin are examples of such products with diabetes (oral antidiabetic agents)
duration of action of approximately 20–36 h. „„The secretagogues
Recombinant DNA technology has also assisted The secretagogues represent the oldest and most
in producing noncrystalline long-acting human commonly prescribed class of antidiabetics [29] .
insulin analogs, glargine and detemir, with sta- The term secretagogues is self-explanatory
bilized insulin–zinc hexamer structures and an regarding the mechanism of action for members

414 Future Med. Chem. (2013) 5(4) future science group

 Antidiabetic agents: past, present & future | Perspective
of the class by inducing insulin secretion from
O O
the pancreatic beta cells. All act primarily R1 S NH C NH R2
through blocking the beta cells ATP-sensitive O
potassium channels, which, in turn, leads to an
increase in calcium influx that stimulates insu- R1 R2
lin release from the pancreas. Secretagogues are Tolbutamide CH3 C4H9
further sub-classified into sulfonylureas and the
non-sulfonylurea (the metiglinides). Tolazamide CH3 N

Sulfonyureas
Chloroprpamide Cl C3H7
Sulfonylureas are a group of drugs with a parent
nucleus derived from the condensation of aryl- Acetohexamide CH3CO
sulfone group with urea moiety, hence the name Cl
sulfonylurea. Sulfonylureas are further sub- O
classified as first and second generation. First Glyburide C NH CH2CH2
generation includes tolazamide, tolbutamide,
acetohexamide, chloropropamide, and second OCH3

generation includes glyburide, glipizide and

Glipizide N O
glimepride. First- and second-generation sulfo-
C NH CH2CH2
nylureas chemically differ in the size of the sub- N
stitution on the aromatic ring (Figure 2) . Drugs
O
with small groups are short acting and require O
multiple daily doses, while drugs with bigger Glimepride
N C NH CH2CH2 CH3
more lipophilc groups are ten-times more potent
and longer acting, once-a-day administered.
Figure 2. First- and second-generation sulfonylureas.
The non-sulfonylurea secretagogues (the
metiglinides) two condensed guanido nuclei, hence the name
The non-sulfonylurea secretagogues, also known biguanides. Three drugs are included in this class:
as the metiglinides, are relatively newer agents metformin, buformin and phenformin (Figure 4) .
than the sulfonyureas with more selectivity to the The drugs lower both basal and postprandial glu-
potassium-ATP channels, used at much lower cose levels in Type 2 diabetes patients by decreas-
doses than the sulfonylureas with less reports ing hepatic glucose production, decreasing intesti-
of hyperinsulinemia. Two metiglinides are nal glucose absorption and increasing peripheral
available: repaglinide and nateglinide (Figure 3) . glucose uptake (GU) and utilization through
improving cell sensitivity to insulin. Effects of
Secretagogues place in therapy these drugs on blood glucose levels are mediated
Sulfonylurea drugs are generally well-tolerated by activating adenosine monophosphate-activated
group of antidiabetic agents and lead to signifi- protein kinase and protein kinase C with net
cant reduction in much of diabetes cardiovas- result of increase GU in skeletal muscle [34,35] .
cular complications. However, their prolonged
use frequently triggers several unwanted adverse
effects including periodic episodes of hyper­
insulinemia, which may lead to sever hypogly- O O
cemia with potential development of coma that CH2 C NH
HO N
may require hospitalization, weight gain and
becoming less effective with time. The meti- O

glinides are much less associated with sulfonyl- Repaglinide

ureas adverse effects; however, they are short
acting and require multiple daily doses. O
C NH
„„The biguanides COOH
Nateglinide
The biguanides represent another class of the
earliest known oral antidiabetic agents. Chemi-
Figure 3. Metiglinides.
cally, members of the class are products with

future science group www.future-science.com 415

Perspective | Mehanna
NH by the ADA to be part of any drug combination
C NH2
Metformin N regimens for diabetes therapy. Metformin is avail-
NH C
NH
able pharma­ceutically as single ingredient tab-
NH lets or in combination products with other oral
C NH2 antidiabetic agents, such as sulfonylureas: Meta-
Buformin N NH C
H glip® (metformin plus glipizide), Glucovance®
NH
(metformin plus glyburide metformin) and with
NH
Phenformin
NH2 insulin sensitizers as Avandmet® (metformin plus
C
N NH C rosiglitazone).
H
NH
„„Insulin sensitizers: thiazolidinediones
Figure 4. Biguanides. PPARs-g agonists/glitazones
All drugs belonging to this class are derivatives
Biguanides place in diabetes therapy of a benzyl-thiazolidinedione (Figure 5) , hence
The development lactic acidosis, elevated plasma the name thiazolidinediones. Members of this
levels of lactic acid, is a serious problem associated class of drugs, troglitazone, rosiglitazone, piogli-
with this class of antidiabetic agents. Lactic aci- tazone, increase cell sensitivity to insulin through
dosis potentially arises from the excessive anero- activating PPARs located in the nucleus. PPARs
bic oxidation of glucose into lactic acid. High are involved in the pathology of several diseases
plasma levels of lactic acid cause inhibition of including diabetes and obesity. The thiazoli-
respiration and could be fatal at times. Members dinediones act as agonist for PPARs, leading to
of the biguanide family differ in the degree of an increase of gene expression for different cells
severity of lactic acidosis they cause, with phen- including hepatic cells. Activated PPARs play
formin being the worse, withdrawn of the mar- an important role in regulating lipids, proteins
ket as a result, and metformin the least. Aside and carbohydrates metabolism and enhance the
from the low potential of causing lactic acidosis action of insulin at insulin-sensitive tissues by
of metformin, the drug is a safe and being recom- increasing GU [36,37] .
mends by the ADA as the first choice for first-
time diagnosed patients with Type 2 diabetes. PPARs agonists place in therapy
Metformin does not cause hyperinsulinemia or PPAR agonists are not effective as monotherapy
hypoglycemia, it lowers only elevated blood sugar for diabetes treatment. They are commonly pre-
levels; so it is described as antihyperglycemic but scribed as add on to other drugs for patients
not as a hypoglycemic agent. The drug does not with insulin resistant diabetes. PPARs agonists
cause weight gain, and it is effective in reducing have several serious adverse effects including:
cardiovascular complications and mortality [29] . weight gain, edema, development of heart fail-
Metformin is efficacious, safe and recommended ure, bone fragility and increased cardiovascular
complications [29] . The FDA recommends warn-
O ing label on cardiovascular safety of these drugs
with contra-indication for patients with existing
O S
O NH heart diseases. Troglitazone is discontinued in
the USA and other world markets due to reports
HO O
of serious hepatotoxicity, and rosiglitazone was
Troglitazone
withdrawn from the European market as well
O
as from New Zealand in 2010 due to increased
N O
S
NH reports of cardiovascular complications [38] . The
suspension of rosiglitazone leaves pioglitazone as
N
O the only remaining insulin sensitizer for clini-
Rosiglitazone
O
cal use in Europe. However, both rosiglitazone
and pioglitazone are still in the USA market.
S
O NH Like metformin, insulin sensitizers are efficient
as antihyperglycemic agents and do not cause
N O hypoglycemia. Rosiglitazone is available as sin-
Pioglitazone
gle tablet ingredient and in combination with
metformin under the trade name Avandamet, as
Figure 5. Thiazolidinediones.
previously mentioned under metformin.

416 Future Med. Chem. (2013) 5(4) future science group

 Antidiabetic agents: past, present & future | Perspective
„„a-glucosidase inhibitors OH
OH
Drugs belonging to this class act primarily by OH OH
inhibiting the enzyme a-glucosidase that hydro- O O O
lyses complex carbohydrates in the GI tract HO OH OH
OH O O
into absorbable glucose. Chemical structures HO
N
HO
H HO HO
of members of the class indicate sugar-like mol- HO
Acarbose
ecules designed for local action in the GI tract OH
with no systemic absorption. Three inhibitors to HO
the enzyme are available: acarbose, miglitol and OH HO
OH OH
voglibose (Figure 6) . HO N OH
HN
OH
a-glucosidase inhibitors place in therapy HO
HO
Members of the class are efficient in reducing Voglibose
OH
Miglitol
postprandial hyperglycemia, safe for oral use,
especially for elderly, with no systemic toxic-
ity. Adverse effects for these drugs are mostly Figure 6. α-glucosidase inhibitors.
gastrointestinal in nature such as flatulence and
diarrhea, probably because of the requirement of Part II: drugs developed during the
multiple dosing [29] . first decade of the 21st century, the
present
„„Summary of drugs available for the The increasing knowledge of the physiology and
treatment of Type 2 diabetes (oral biochemistry of the diabetes disease unraveled
antidiabetic agents) several new targets to design new antidiabetic
drugs with different structural features and dif-
n The secretagogues: ferent mechanisms of action. The current part
Sulfonylureas:
„„ of the review addresses the medicinal chemistry
First generation: tolbutamide
„„
of the new antidiabetic drugs developed through
(Oramide®, Orinase®), tolazamide the first decade of the 21st century, including:
(Tolamide®, Tolinase®), acetohexamide
(Demylor®), chlorpropamide n The GLP-1 analogs;
(Diabenese®); n DPP-IV inhibitors;
Second generation: glipizide
„„
n Amylin analogs;
(Glucotrol®), glyburide (Micronase®,
Diabeta®, Glynase®), glimepride n SGLT2 inhibitors.
(Amaryl®).
Non-sulfonylureas (Metiglinides):
„„

Residue 7
Repglinide (Prandin®), nateglinide
„„

NH2
(Starlix®).
n The bigaunides: His Ala Glu Thr Phe Thr Ser Asn
Gly
Metformin (Glucophage®), buformin,
„„

phenformin. Ser Val

Glu Leu Val Ser
Gln Gly
Ala
n Insulin sensitizers (the thiazolidindiones):
Troglitazone (Rezulin®), pioglitazone
„„
Ala Trp Leu Val
(Actos®), rosiglitazone (Avandia®). Lys Glu Phe ILe Ala

n The a-glucosidase inhibitors: Lys

Arg Gly
Acarbose (Prelose®), miglitol (Glyset®),
„„ Gly
viglibose (Voglip®).
COOH Residue 34
n Multi-ingredient formulations: Residue 37
Metformin+ glyburide (Glucovanc),
„„

metformin + glipizide (Metaglip), Figure 7. GLP-1, a 31-amino acid hormone (7–37 residues of the precursor)
with N-terminus histidine and C-terminus glycine.
metfotmim + rosiglitazone (Avandamet).

future science group www.future-science.com 417

Perspective | Mehanna
Residue 7 as a potential therapeutic agent to treat diabetes.
NH2 GLP-1 is biosynthesized as a precursor polypep-
tide chain consisting of 37 amino acids. The
His Ala Thr Phe Thr Ser Asn hormone is activated by breaking of six amino
Glu Gly
acid residues from the N-terminal to give two
Val active fragments, GLP-1, a 31-amino acid residue
Ser Ser
Gln Gly Glu Leu Val (7–37) with N-terminus His7 and C-terminal
Ala
Gly37 (Figure 7) , and a 31-amino acid fragment
GLP-1(7–37) with the Gly37 carboxylic group
Ala Trp Leu Val converted into an amide group (Figure 8) [42] .
Lys Glu Phe ILe Ala
Both active forms of GLP-1 undergo deacti-
Lys vation by the amino-peptidase enzyme, DPP-IV,
Arg Gly through removal of two terminal amino acids
Gly
from the N-terminus end to give inactive GLP-1
CONH2 fragments with two amino acid residues less than
Residue 34
Residue 37 the active forms (fragments 9–37, and 9–36-Gly-
amide, respectively). The deactivation of GLP-1
Figure 8. GLP-1-amide, a 31-amino acid hormone (7–37 residues) with hormones occurs rapidly and results in a very
N-terminus as histidine, and C-terminus glycine residue 37 converted to short plasma half-life of 1–2 min for both active
glycine-amide.
forms of the GLP-1 hormone. The short half-life
of GLP-1 makes such natural hormones of no
„„GLP-1 analogs or the incretin mimetics potential use as therapeutic agents [43] . The pep-
Incretins GLP-1 tide sequence of GLP-1 reveals that the principal
Incretins are polypeptide hormones secreted by reason of why GLP-1 is so susceptible to degrada-
the L-cells of the gastrointestinal mucosa. Their tion by DPP-IV is the presence of the amino acid
function is to induce insulin release from the alanine in the penultimate position of its chain.
pancreatic beta cells in response to carbohydrate Substitution of alanine with various amino acids
absorption from the GI tract [39] . The amino acid resulted in more stable peptides toward the deg-
sequence of the incretins has high similarity to radation effects of DPP-IV [44] . The interest in
that of the hormone glucagon, so they are com- GLP-1 insulinotropic activity led to the develop-
monly called GLPs. The stimulatory effects of ment of two new classes of antidiabetic agents
incretins on insulin release from the beta cells that enriched the arsenal of available drugs to
are identical to those produced in response to treat Type 2 diabetes. First, is the GLP-1 analogs
blood glucose elevation [40,41] . GLP-1 is an incre- (incretin mimetics) that resist enzymatic deactiva-
tin that drew much attention in the past decade tion and, second, is the DPP-IV inhibitors, which
prolong the plasma half-life of native GLP-1.
NH2
GLP-1 analogs or incetin mimetics
Residue Thr Ser Asp
His Gly Glu Gly Thr Phe Exenatide (Byetta ®)
1
Exenatide is a 39-amino acid polypeptide that
Lys Ser Leu was first isolated from the venom of a Gila Mon-
Glu Glu Glu Met Gln
Ala ster [45] . The polypeptide has a 53% homology
to GLP-1. In 2004, exenatide was the reported
as the first GLP-1 analog with significant clini-
Val Trp Leu Lys
Arg Leu Phe ILe Glu cal effects in controlling Type 2 diabetes [46] .
Exenatide was introduced to the US market in
Asn 2005 under the trade name Byetta®. The poly-
Ser Gly Gly
Pro Ala Gly Ser Pro peptide chain of exenatide differs from that of
GLP-1 in 16 amino acid residues. The relative
Pro stability of exenatide toward enzymatic hydro-
Pro Ser CONH2 lysis by DPP-IV attributed to the substitution of
the penultimate alanine residue of GLP-1 with
Residue 39 a Gly in exenatide. Exenatide has its C-39 Ser
terminal residue carboxyl group converted to an
Figure 9. Exenatide structure, a 39-amino acid GLP-1 analog
amide (Figure 9) .

418 Future Med. Chem. (2013) 5(4) future science group

 Antidiabetic agents: past, present & future | Perspective
Although more stable toward enzymatic NH2
hydrolysis than native GLP-1, exenatide has a
short biological half-life of 26 min after intra- Thr Ser Asp
His 7 His Ala Glu Gly Thr Phe
venous administration, extends to 3 h after sub-
cutaneous administration. The short half-life of Ser Val
Glu Leu Val Ser
exentatide, even after subcutaneous adminis- Ala Gln Gly
tration, requires multiple dose administration.
The rapid clearance of exenatide by the renal
Ala
system contributes its short half-life. The drug Lys Glu Palmitoyl
clearance by the kidney poses risk for patients
with renal insufficiency. The short half-life of Glu
Lys 26
exenatide requires multiple daily injections,
which may become an issue for patient compli- Trp Leu
Phe ILe Ala Val
ance. Another major disadvantage of exenatide
is the potential development of allergic reactions.
The development of allergic reaction is probably Arg
Arg Gly
Gly
attributed to the high percentage of dissimilarity
(53% homology) to the native GLP-1. The aller-
COOH Residue 34
gic reactions, however, did not cause increase
in immunological side effects after 30 weeks of
Figure 10. Liraglutide, a 31-amino acid GLP-1 analog with lysine 26
treatment of patients with Type 2 diabetes [47] . conjugated through it gamma amino group with glutamic acid residue
Byetta’s multiple injections dosing requirement, acylated with palmitoyl group at its amino group.
together with its potential problems for patients
with kidney insufficiency prompted the search
of newer GLP-1 analogs with less of exenatide of liraglutide were initially reported in 2006
drawbacks. [48] , and several more reviews have been recently
published [49–51] .
Liraglutide (Victoza ®)
Liraglutide, a new GLP-1 analog, specifically GLP-1 analogs (incretin mimetics) place in
designed to be void of much of exenatide therapy
unwanted properties. The drug has a 31-amino Incretin analogs as a new class of antidiabetic
acid polypeptide chain, fraction 7–37 of GLP- drugs need further investigation for efficacy
1, with 97% homology to the native GLP-1. and safety in diabetes therapy. Like metfor-
Chemically, liraglutide is N26-(Hexadecanoyl- min, GLP-1 analogs have unique properties
l-g-glutamyl)-(34-l-Arg) GLP-1-(7-37)-pep- over all other antidiabetic drugs in causing
tide. Major chemical differences between lira- weight loss and not gain. GLP-1 analogs also
glutide and the native GLP-1 are the replace- reported to improve beta cell mass and func-
ment of Lys34 with Arg and the attachment tion [29] . The adverse effects are of gastrointes-
of a hexadecanoyl-l-g-glutamyl group to the tinal nature, including nausea vomiting and
Lys26 residue (Figure 10) . The high percentage diarrhea. Several cases of development of acute
homology of liraglutide to the native peptide pancreatitis recently reported. As a new class
eliminated much of the allergic reactions. On of antidiabetic agents, the overall long-term
the other hand, the hexadecanoyl-l-g-glutamyl safety profile is unknown and needs future
substitution at Lys26 increased liraglutide assessment [29] . GLP-1 analogs are currently
binding to the plasma proteins, a feature that available as individual products; and a fixed
significantly decreased its renal clearance. The
F
increase of liraglutide plasma protein bind-
F
ing by acylation with the palmitoyl group not NH2 O
only decreased its renal clearance, but also pro- N
N
tected the drug from enzymatic deactivation N
F N
by DPP-IV. Liraglutide has plasma half-life of
8 h after intravenous administration, given as a F F
F
single daily injection. Liraglutide was approved
for clinical use in the USA in 2010 under the
Figure 11. Sitagliptin.
trade name Vectoza®. The antidiabetic effects

future science group www.future-science.com 419

Perspective | Mehanna

N introduced to the market. The drug structure

(Figure 11) depicts two major pharmacophores
that were found to be essential for optimum
HO the DDP-IV inhibitory activity: a beta amino
N
N
amide functionality and a triazolo piperazine
H fused hetero­c ylic ring system to which a triflu-
O romethyl as an electron withdrawing group is
attached. The incorporation of the piperazine
Figure 12. Vidagliptin. ring into fused system was designed to slow
down the metabolism of the drug through the
dose combination of liraglutide with insulin is piperazine ring system. The fused ring system
under development [52] . increased sitagliptin oral bioavailability in
comparison to other similar analogs without
„„DPP-IV inhibitors fusion.
DPP-IV The trifluromethly group, with its electron-
DPP-IV is one of nine known members of the withdrawing nature, was also found to be opti-
dipeptidyl peptidases family (a subclass of the mum group for high oral bioavailability. Sita-
larger Ser proteases family). DPP-IV differs from gliptin has oral bioavailability of 87% [42] . In
all other dipeptiyl peptidase members in having addition to the effect of these structural enti-
its catalytic triad inversely ordered as Ser-Asp- ties on oral bioavailability, molecular modeling
His. The enzyme selectively inactivates GLP- revealed that the two groups have specific bind-
1by removing the dipeptide His-Ala from the ing sites on the catalytic pocket of DPP-IV. Sita-
N-terminus of its 31-amino acid peptide (residues gliptin is a potent and selective DPP-IV inhibitor
7–37) to give a remnant 29-amino acid chain useful for the treatment of patients with Type 2
GLP-1(9–37) as an inactive fragment [42,53] . diabetes mellitus. Adverse effects include con-
stipation, nausea, nasopharyngitis, urinary tract
DPP-IV inhibitors infections and dizziness. The preclinical trial
Inhibition of DPP-IV became a target for devel- data for sitagliptin, implicate the drug in the
oping new drugs for diabetes mellitus treatment. development of acute pancreatitis [58] .
DPP-IV inhibition allows GLP-1 to survive
longer in plasma and exerts more of its insu- Vidagliptin (Galvus ®)
lin release stimulatory activities. In addition Further efforts to develop more DPP-IV
to continuous need for more potent inhibitors, inhibitors led to the discovery of a new class of
two other major challenges face medicinal chem- DPP-IV inhibitors known as the cyanopyrro-
ists in designing inhibitors for DPP-IV. First, lidines. Vidagliptin (Figure 12) [54,59] , represents
is to selectively inhibit only type IV (and not the prototype drug of this class. The cyano
the other eight types of dipeptidyl peptidases); group, in addition to its potential role as the
second, is the duration of action, since GLP-1 electron-withdrawing group as discussed with
should exist intact over 24 h period to manifest sitagliptin, was found to act as an electrophile
a significant control on blood sugar levels [54] . that reacts covalently with the Ser630 of DPP-
Several reviews on the medicinal chemistry of IV active site. The resulting imidate adduct
DPP-IV inhibitors and their use in controlling leads to irreversible inactivation of the enzyme
diabetes are available in literature [42,49,53–56] . and eventually to a longer duration of action.
Additional structural features of vidagliptin
Sitagliptin (Januvia ®) molecule includes a Gly entity substituted with
Sitagliptin [57] was the first developed DPP-IV an adamantyl group.
inhibitor and the first of this class to be Vidagliptin metabolism occurs through
hydrolysis of the cyano group, probably catalyzed
CN OH by DPP-IV itself. Vidagliptin is also metabolized
NH2 by the formation of a cyclized diketo piperazine
N
product, resulting from the interaction of the
O Gly amino group with the reactive cyano car-
bon. Vidagliptin has oral bioavailability of 85%
[42] and was approved for clinical use in Europe
Figure 13. Saxagliptin.
in 2008 but is not yet available in the USA.

420 Future Med. Chem. (2013) 5(4) future science group

 Antidiabetic agents: past, present & future | Perspective
Saxagliptin (Onglyza ®)
O
Saxagliptin is another cyanopyrrolidine DPP-IV
N N
inhibitor with very similar structural features to N
N
vidagliptin except that the adamantyl group is on N
N
O N
the alpha carbon atom of the amide group and NH2
the cyanopyrrolidine ring forms a bicylo structure
with a cyclopropyl group (Figure 13) [59,60] .
The bicyclic structure increased the metabolic Figure 14. Linagliptin.
stability of the cyano group on the pyrrolidine
ring and inhibited the formation of the diketo- The pharmacology, pharmacokinetics, efficacy,
piperazine metabolite, probably by altering the tolerability, drug–drug interactions, contra­
positioning of the cyano and the amino groups indications and dosage of linagliptin, have been
into unfavorable position to form cyclic struc- recently reviewed in 2012 [65,66] . The drug was
ture. Saxagliptin metabolism occurs by further approved for clinical use in 2011 as a stand alone
hydroxylated of the adamantyl ring system into therapy or as an adjunct with other antidiabetic
a dihydroxy active metabolite. The latter, explains agents. A combination formulation of the drug
the long duration of action of saxagliptin and pro- with metformin, was investigated and reported
vides advantage over vidagliptin as a long-acting to be more efficacious in controlling blood sugar
drug suitable for once-a-day administration. The level than the single therapy [67] .
drug has 75% bioavailability after oral adminis-
tration. Saxagliptin was approved for clinical use Alogliptin (Nesina ®)
in 2009 and its value in treating Type 2 diabetes Alogliptin (Figure 15) is a new DPP-IV inhibi-
has been recently reviewed [61,62] . tor developed in 2007 and recently approved for
clinical use in Japan in 2012 under the trade
Linagliptin (Tradjenta ®) name Nesina® [68] . The drug is not yet avail-
Further search for newer DPP-IV inhibi- able in the USA. Structurally, the drug, with
tors resulted in the discovery of linagliptin its pyrimidine and piperidine nuclei, and the
(Figure 14) . The drug structure is a xanthine cyano group on the benzene ring, appears to be
nucleus substituted with quinazoline ring a hybrid design of vidagliptin and linagliptin.
system at N-1, a butynyl group at N-7, and a Information on the drug kinetics and its clinical
3-aminopiperidine group at C-8. Each of the value is not available yet.
three groups was found to play an essential role
in linagliptin binding to the enzyme catalytic DPP-IV inhibitors place in therapy
site [63] . The drug characterized by being more In general, DPP-IV inhibitors are well toler-
potent than other DPP-IV inhibitors (oral dose ated, with low adverse effects [53] . Converse to
5 mg, compared with sitagliptin 100 mg and GLP-1 analogs, DPP-IV inhibitors do not cause
vidagliptin 50 mg) and equipotent with saxa- weight loss and have neutral effect on body
gliptin (5-mg oral dose). However, renal excre- weight. However, as with GLP-1 analogs, they
tion of saxagliptin makes it shorter acting the do not cause hypoglycemia. DPP-IV inhibi-
linagliptin [53] . In addition, when tested in tors occasionally reported to cause urticaria,
animal models, linagliptin reported to have an angioneuretic edema and cases of pancreatitis
IC50 of 1.0 nM reflecting higher selectivity than observed. As a new class of antidiabetic agents,
sitagliptin (IC50 18.0 nM) tested under the same the overall long-term safety profile is unknown
model [54] . Linagliptin also is characterized by and future assessment is needed [29] .
having a very long half-life of 131 h, which gives
it advantage over other DPP-IV inhibitors by
sustaining the inhibitory effect on the enzyme O CN
for prolonged period that could reach 24 h, a
duration that fulfills the need for prolonged N N

survival of native GLP-1 to observe significant O N

clinical effects [42,64] .
The long half-life of linagliptin is mainly
H2N
attributed to its strong binding to plasma pro-
teins, which, in turn, results in reduced hepatic
Figure 15. Alogliptin.
metabolism and extended duration of action [65] .

future science group www.future-science.com 421

Perspective | Mehanna
Incretin-based therapy on the horizon acid polypeptide with disulfide bridge between
Several new pharmaceutical products of incretin Cys2 and Cys7 (F igure 16) [73] . The interest
analogs are currently awaiting approval for clini- in amylin as a potential therapy for diabetes
cal use in the USA. A recent review by Jones and arose from its synergistic actions to insulin in
Gouch [69] addressed the most recent advances in both Type 1 and Type 2 diabetes. However,
incretin-based therapies. The report lists several the chemical nature of native amylin, as a
new products primarily based on formulating highly insoluble protein, and its polymeriza-
incretin analogs in a long acting adduct for- tion into long stable fibers precluded its use as
mulations for once-a-day, or even once-a-week a therapeutic agent. A search for soluble amylin
use. The new products include: lixisenatide analogs started in the late 1990s through the
(Lyxumia®), an adduct with plasma protein for early 21st century.
once-a-day use; albiglutide (Syncria®), a GLP-1
dimer fused with human albumin for once-a- Amylin analogs
week administration; dulaglutide, a GLP-1 ana- The observation that the aggregation of amylin
log fused to FC antibody fragment for once a into fibers is a species selective and the amylins
week use. of rats and mice, unlike human amylin, do not
polymerize into amyloid fibers, triggered inter-
„„Amylin & amylino-mimetics est in studying the difference in the polypeptide
Amylin, the hormone structures of human versus rodent amylin [74] .
Amylin is a polypeptide hormone that was first The study revealed the presence of three Pro
discovered in 1987 during the purification and residues at positions 25, 28 and 29 in the rodent
characterization of amyloid-rich pancreas iso- amylin, whereas human amylin has these resi-
lated from Type 2 diabetic patients [70] . Amy- dues as alanine, Ser and Ser at the corresponding
lin, also called islet amyloid polypeptide, is positions. The three Pro amino acids found to
synthesized in the beta cells of the pancreas be the primary reason for the rodent amylin not
and co-secreted with insulin in a ratio of 1:100. to polymerize [75] .
As with insulin, amylin is involved in control-
ling blood glucose level. It delays gastric emp- Pramlintide (Symlin®)
tying and suppresses glucagon secretion with a The effect of the Pro residues in rodent’s amy-
net result of a decrease in endogenous glucose lin on its water solubility triggered the develop-
output from the liver [71] . Amylin also regu- ment of a human amylin analog with three Pro
lates the desire to eat and reduce caloric intake amino acids at the same positions 25, 28 and 29
through specific centers in the brain; and to replace the original Ala25, Ser28 and Ser29
implicated in the progression of Alzheimer dis- respectively. Indeed the strategy succeeded in
ease [72] . Native human amylin is a 37-amino producing a water-soluble amylin analog. Prami-
linitide (Figure 17) [76,77] , as the first water-soluble
analog for human amylin, was introduced to the
NH2
market in 2005 under the trade name Symlin®.
Pramlinitide modulates gastric emptying and
Residue Thr Ser Residue prevents postprandial glucagon secretion, both
Tyr Thr Asn Gly Val Asn
37 Ser 29 of which lead to decreased caloric intake and
Residue lead to potential weight loss. The role of pram-
Leu Ser
Phe Gly Ala ILe 28 lintide in diabetes control has been reviewed in
Asn Asn
Ser
2007 [78] , and, more recently, in 2011 [79] and
2012 [80] .
Ser Ala Leu Arg
His Val Leu Phe Asn
Pramlinitide place in therapy
Pramlintide was approved by the FDA to treat
Gln
Ala Thr both Type 1 and Type 2 diabetics. Pramlint-
Thr Cys
Lys Cys Asn Thr Ala
ide allows patients to use less insulin in the
case of Type 1 diabetes. In addition to insulin
COOH S S and its analogs, pramlintide is the only newly
approved drug by the FDA to lower blood sugar
in Type 1 diabetics since insulin discovery in
Figure 16. Human amylin, a 37-amino acid polypeptide.
the early 1920 [76] . Pramlinitide lowers average

422 Future Med. Chem. (2013) 5(4) future science group

 Antidiabetic agents: past, present & future | Perspective
blood sugar levels, and substantially reduces the NH2
large unhealthy rise in blood sugar that occurs
right after eating. The drug has a short half-life Residue Thr Pro Residue
Tyr Thr Asn Gly Val Asn
37 Ser 29
of approximately 48 min due to its fast renal
excretion [77] . Pro Residue
Pro ILe Leu 28
Asn Asn Phe Gly
Ser

„„SGLT2 inhibitors
SGLT2 Ser Ala Leu Arg
His Val Leu Phe Asn
SGLTs are group of proteins that exist in both
small intestine and the renal proximal tubules. Gln
Two types of the transporters are identified: Ala Thr
Thr Cys
Lys Cys Asn Thr Ala
SGLT1, which exists mainly in the small intes-
tine, and SGLT2, which exists mainly in the
renal tubules. SGLT2 regulates the reuptake of COOH S S
the majority of glucose filtered in urine. The
kidney SGLT2 has been considered a target for Figure 17. Pramlinitide, a 37-amino acid soluble amylin analog.
therapeutic intervention for diabetes treatment
[81–84] . Inhibition of SGLT2 leads to an increase „„Summary of the drugs covered under
in glucose excretion (glucoseurea) and provides Part II (the present antidiabetic agents)
a unique mechanism to lower elevated blood n GLP-1 analogs (glucagon-like peptides

glucose levels in diabetes. analogs):

Exenatide (Byetta), liraglutide (Victoza).
„„
Dapagliflozin (Foxiga ®)
DPP-IV inhibitors (dipeptidyl peptidase
„„
Several inhibitors for SGLT2 transporters have
IV inhibitors):
been successfully developed and underwent pre-
clinical evaluation [85–87] . The results of the pre- Sitagliptin (Januvia®), vidagliptin
„„

clinical evaluation led to dapagliflozin (Figure 18) Galvus®), saxagliptin (Onglyza®),

as the first member of the class approved for clin- linagliptin (Tradjenta), alogliptin
ical use in Europe in 2012 under the trade name (Nesina).
Foxiga®. Data of pharmaco­logical, pharmacoki- Amylin analogs:
„„

netic and pharmacodynamic properties, clinical Pramlinitide (Symlin).

„„

safety and efficacy, was undergoing review by the n SGLT2 inhibitors (sodium dependent glucose
FDA for potential approval to use in the USA transporter inhibitors):
[85] . However, the agency has recently rejected Dapagliflozin (Foxiga);
„„

dapagliflozin citing concerns about possible liver Canagliflozin (Invokana).

„„

damage and elevated rates of bladder and breast

cancer.
Part III: the future (future targets for
design of new antidiabetic agents)
Canagliflozin (Invokana ®)
Considering the importance of antidiabetic agents
Recently, the FDA has approved canagliflozin
and their role in controlling diabetes-related mor-
(Figure 19) [86] , another SGLT2 inhibitor, for use
tality, the search for newer anti­diabetic drugs to
in the USA under the trade name Invokana®.
treat the only recognized non-infectious disease by
Canagliflozin is the first SGLT2 inhibitor to
the WHO as an epidemic disease continues. The
be approved for use in the USA, however, the
revelation and discovery of involvement of more
FDA panelists who voted for its approval raised
hormonal and enzymatic systems in the process
concerns regarding low levels of heart attack,
stroke and urinary tract infections seen in the OH
first year of clinical testing. The panelists rec- OH
ommended tracking of long-term prognosis of O

those problems. OH
Recent research to develop newer SGLT2 OH
O Cl
inhibitors revealed a series of indolylxylo-
sides with potent inhibitory activity for the
Figure 18. Dapagliflozin.
transporter [87] .

future science group www.future-science.com 423

Perspective | Mehanna
inhibition as a potential new approach to treat
OH
HO OH
diabetes [96–102] .

F S
O
OH „„GP inhibitors
GP is a typical allosteric protein that plays a cen-
tral role in glycogen metabolism. It is increas-
ingly becoming an interesting field to discover
Figure 19. Canagliflozin. GP inhibitors as potential antidiabetic drugs. A
full review on advances in the design of inhibitors
of controlling glucose blood level are on the rise. with chemical structures of different allosteric
Several of such hormones, channels, transport modulators has been published in 2011 [103] .
proteins and enzymes are set as targets for future
drug design for newer antidiabetic agents. Among „„a-amylase inhibitors
these targets and approaches, glucagon antago- a-amylase is a pancreatic digestive enzyme
nists, protein-phosphatase inhibitors, GP inhibi- involved in the digestion and breakdown of
tors, carbohydrates digestive enzyme inhibitors, ingested carbohydrates. The enzyme plays a piv-
metal complexes, leptin, aldose reductase inhibi- otal role in increasing blood glucose level. Several
tors, GK activators, natural products, immuno- plant extracts found to have inhibitory effects on
logical approaches, beta cells preservation and the enzyme activity. Although natural products
heterocyclic molecules with antidiabetic activity. are safer agents than synthetic drug, however,
Part III of this article addresses the rationale of rational drug design is possible to develop selec-
considering each of the above-mentioned targets tive inhibitors based on lead structures found in
as a potential research area to develop new anti- the plant extracts [104,105] .
diabetic agents. Detailed below are 12 current
research areas that can result in developing newer „„Metal complexes
antidiabetic agents. Biological traces of metals such as iron, zinc,
copper, vanadium and manganese play an essen-
„„Glucagon antagonists tial role to the life and health of humans. The
Glucagon is a polypeptide hormone produce by success of platinum complexes in cancer chemo-
the alpha islet of the pancreas. Its relationship to therapy has rapidly grown interest for medicinal
insulin is regulatory. When glucagon is released chemists to develop inorganic pharmaceuticals
it stimulates the breakdown of liver glycogen into for diabetes treatment. Recent reports have
glucose; leading to elevation of blood sugar levels. emphasized the potential use of zinc complexes
Glucagon stimulates glycogen breakdown (gly- [106] or vanadium [107] for treatment of diabetes.
cogenolysis) by binding to specific receptors on
the hepatocytes. The increase in blood glucose „„Leptin
level resulting from the glucagon action stimu- Leptin is a polypeptide hormone that is pro-
lates insulin release from the beta cells of the pan- duced by the adipose tissue. It regulates several
creas. Recent research directed toward the devel- biological processes including appetite control,
opment of glucagon antagonists to counter act body weight and lowering blood glucose levels.
the high basic glucagon levels normally observed It was documented that long-term use of leptin
with diabetic patients. Several compounds with as a replacement therapy, improved glycemia
diverse chemical nuclei including biphenyl, phe- control, increased tissue sensitivity to insulin
nyl pyridines, triaryl imidazoles, triarylpyrroles, and a decreased plasma triglyceride levels. The
trisubstituted ureas and benzimidazoles are under involvement of leptin in regulating glucose
evaluation as glucagon antagonists [88–95] . metabolism makes it an attractive target for
new antidiabetic drug development. A review
„„Protein tyrosine phosphatase inhibitors on leptin potential use as antidiabetic drug was
Insulin receptors become more sensitive to insu- published recently [108] .
lin when they are phosphorylated. Protein tyro-
sine phosphatase is an enzyme that hydrolyzes „„Aldose reductase inhibitors
phosphorylated insulin receptors. Inhibition of The development and progression of chronic
the enzyme prolongs the phosphorylation status complications in diabetic patients, such as reti-
and consequently tissue sensitivity to insulin. nopathy, nephropathy, neuropathy, cataracts,
Numerous articles addressed tyrosine kinase and stroke, are related to the activation and/or

424 Future Med. Chem. (2013) 5(4) future science group

 Antidiabetic agents: past, present & future | Perspective
overexpression of the enzyme aldose reductase, „„Immunological approach
which is a member of the aldo-keto reductase Type 1 diabetes is viewed as an autoimmune
superfamily [109] . The initial finding correlating disease that results from the targeted self-
aldose reductase inhibition with diabetes was destruction of the insulin-secreting beta cells of
first reported by Stribling and Perkins in 1986 the pancreas. Over the past two decades, the
[110] . Studies demonstrated that inhibition of the increased understanding of the pathogenesis of
enzyme improves the diabetes long-term compli- the disease has led to the development of new
cations [111] . Several articles reported the devel- immune-modulatory treatments using immuno­
opment of selective inhibitors to the enzyme for suppressant drugs. Unfortunately, no entity has
potential use as antidiabetic agents [112–114] . yet received a regulatory approval. Tooly et al.
published in 2012 a lengthy review [130] on
„„GK activators new and future immune-regulatory therapy in
GK is a member of the hexokinase family of Type 1 diabetes. This area needs more efforts to
enzymes that are responsible for the phosphory- conduct aggressive research [130] .
lation of glucose into glucose-6-phosphate [115] .
The latter is the active form of the glucose utilized „„Beta cell preservation & regeneration
by cells to produce energy. GK plays a key role Over the past decade, the knowledge of beta-
in glucose homeostasis in cells that express this cell biology has expanded with the use of
enzyme, such as b-cells and hepatocytes. The new advancement in scientific techniques and
enzyme activates glucose oxidation in the beta strategies. Growth factors, hormones and small
cells and raises the threshold of insulin secretion molecules were found to enhance beta-cell
in response to glucose concentration which leads proliferation and improve its function. Stem
to hyperinsulinemia [116] . It is also reported that cell technology and its research into the devel-
GK activation repairs defective bioenergetics of opmental biology of the pancreas have yielded
islets of Langerhans isolated from Type 2 dia- new methods for in vivo and in vitro regenera-
betic patients [117] . Comprehensive reviews on GK tion of beta cells. Novel approaches have been
activation therapeutic potential has been recently introduced to preserve and enhance the beta cell
published by Matschinsky and colleagues [118,119] . function, increase the expression of insulin gene
Because of insulinotropic effects of activating and minimizing beta cell loss and dysfunction
the enzyme and its stimulatory effect on glyco- present a very promising future trend in treat-
gen synthesis in the liver, consequently decreases ing diabetes in general and Type 1 in particu-
blood glucose levels, development of activators lar. Karadimos et al. published a comprehensive
for the enzyme is a potential new strategy to treat review on the subject [131] and Ruan et al. pro-
Type 2 diabetes. The efficacy of GK activators was posed a mechanism to prevent beta cell death in
recently assessed along with other potential anti- Type 1 diabetes [132] .
diabetic agents in a recent review [120] . Piragliatin
was recently reported to be the first GK activator „„Miscellaneous research for the
to be studies for antidiabetic activity [121] . development of small-molecule antidiabetic
agents
„„Natural products Several recent research articles have been found
Despite the progressive use of synthetic drugs for in the literature addressing the design, synthe-
diabetes treatment, the use of herbal remedies is sis and biological evaluation of new organic
gaining increasing interest and becoming a very compounds with various heterocyclic nuclei for
important alternate medicinal class. Synthetic potential antidiabetic activity. Examples are: the
drugs have numerous drawbacks, which may have benzimidazoles [133,134] , pyrazolines [135] , oxa-
contributed to such search for alternate medicines. diazole [136,137] , triazoles [138] , thiazolidinediones
A sizable group of herbal products have been [139] and oxathiazines [202] .
extensively studied and looked at as an alternative
medicine to treat diabetes. The easy availability, „„Summary of potential targets covered in
affordability and low side effects compared with Part III for future drug design of newer
the synthetic drugs rendered natural product an antidiabetic agents
attractive destination for diabetes researchers.
Several publications on the antidiabetic activity n Glucagon antagonists;
of variety of plants and natural products have
appeared recently in literature [122–129] . n Protein tyrosine phosphatase inhibitors;

future science group www.future-science.com 425

Perspective | Mehanna
n Glycogen phosphorylase inhibitors; in the future. Natural products, in addition
to being more affordable in poor parts of the
n a-amylase inhibitors;
world, have considerably less adverse effects
n Metal complexes; compared with synthetic drugs. The author
also believes that Type 1 diabetes treatment
n Leptin;
is a challenge that needs more attention from
n Aldose reductase inhibitors; researchers. The total dependence on insulin
for treatment of Type 1 diabetes, with the
n Glucokinase activators;
associated high risk of hyperinsulinemia and
n Natural products; the inconvenience of its repeated injections,
render insulin therapy unsafe. The amylin
n Immunological approaches;
analogs look promising in solving this prob-
n Beta cells preservation; lem. Reports indicate Type 1 diabetic patients
concurrently administering amylin analogs
n Miscellaneous heterocyclic molecules with
and insulin, needed much less insulin than
antidiabetic activity.
using insulin alone. The author expects future
breakthrough in the treatment and prevention
Future perspective of Type 1 of diabetes through organ trans-
Diabetes mellitus will continue to be a world- plant, stem cell research, beta cell preservation
wide epidemic problem and its cardiovascular or immunological approaches.
complications will remain the major cause of
mortality across the globe. The development Acknowledgments
of safer and more potent drugs will grow con- The author would like to thank The Massachusetts College
sidering the continuous unravel of aspects of Pharmacy and Health Sciences for allowing time to write
pertaining to the disease pathology and prog- the article. The author also would like to offer special thanks
nosis that were previously unavailable. New to S Mufti and J Faulhaber, for help in locating and order-
knowledge regarding several enzyme systems ing the required references.
implicated in the disease pathology, coupled
with fast-paced advancement in biotechnol- Financial & competing interests disclosure
ogy raise expectations and hopes for develop- The author has no relevant affiliations or financial involve-
ment of safer drugs in the future. The author ment with any organization or entity with a financial inter-
also believes that among drug classes that est in or financial conflict with the subject matter or materi-
will witness more development are the classes als discussed in the manuscript. This includes employment,
addressed in part II of the article including consultancies, honoraria, stock ownership or options, expert
GLP-1 analogs, DPP-IV inhibitors, amylin t­estimony, grants or patents received or pending, or
analogs and SGLT2 inhibitors. Natural prod- royalties.
ucts are also promising alternate therapy and No writing assistance was utilized in the production of
may play a significant role in treating diabetes this manuscript.

Executive summary
„„ Diabetes mellitus as a worldwide epidemic disease that expected to continue to be so for decades to come according to the WHO.
„„ Cardiovascular complications of diabetes mellitus are serious and constitute to be major cause of death for diabetic patients around the
globe.
„„ Laboratory tests for diabetes diagnosis have shifted from the traditional oral glucose tolerance test to the measurement of HbA1c as the
only significant diagnostic test for diagnosing the disease and assessing its prognosis.
„„ A more challenging problem exists with Type 1 diabetes due to the total dependence on insulin for therapy. Insulin therapy carries the
risk of development of hyperinsulinemia and potential hypoglycemia incidences.
„„ Cardiovascular complications of diabetes mellitus are very devastating adverse effects for diabetes mellitus and the need for newer drugs
with less of such complications deem necessary.
„„ Diabetes treatment with antidiabetic medications, recommended for use when diet and exercise options are exhausted.
„„ The American Diabetes Association (ADA) guidelines for diabetes treatment emphasize the importance of diet and physical activity as
the first line of therapy for Type 2 diabetes. The ADA recommends metformin as the first therapy for newly diagnosed patients with
Type 2 diabetes; followed by addition, if needed, of one or more of drugs from other classes. The ADA recommends combination
therapy in all cases.

426 Future Med. Chem. (2013) 5(4) future science group

 Antidiabetic agents: past, present & future | Perspective
13 Watanabe K, Thandavarayan RA, Gurusamy 25 Ovalle F. Cardiovascular implications of
References
N et al. Role of 14–13–3 protein and antihyperglycemic therapies for Type 2
Papers of special note have been highlighted as:
n of interest
oxidative stress in diabetic cardiomyopathy. diabetes. Clin. Ther. 33(4), 393–407 (2011).
nn of considerable interest
Acta Physiol. Hung. 96(3), 277–287 (2009). nn Provides useful information of the risk
1 American Diabetes Association. Diagnosis 14 Nwose EU, Jelinek H, Richards RS, Kerr PG. factors caused by antidiabetic drugs.
and classification of diabetes mellitus. Erythrocyte oxidative stress in clinical
26 Marcinak JF, Viswanathan P, Arora V, Roebel
Diabetes Care 35(Suppl. 1), S64–S71 (2010). management of diabetes and its cardiovascular
LE, Strack TR, Leifke E. Shift from surrogate
complications. Br. J. Biomed. Sci. 64(1), 35–43
2 Potenza MA, Nacci C, Gagliardi S, end point to outcome trials: implications for
(2007).
Montagnani M. Cardiovascular cardiovascular safety assessment in
complications in diabetes: lessons from 15 Haidara MA, Yassin HZ, Rateb M, Ammar H, development programs for antidiabetic drugs.
animal models. Curr. Med. Chem. 18(12), Zorkani MA. Role of oxidative stress in Clin. Pharmacol. Ther. 91(3), 514–520 (2012).
1806–1819 (2011). development of cardiovascular complications
27 Sheetz MJ, King GL. Molecular
in diabetes mellitus. Curr. Vasc. Pharmacol.
3 Kakadiya JL, Shah NJ. Cardiovascular understanding of hyperglycemia’s adverse
4(3), 215–227 (2006).
complications of diabetes review. effects for diabetic complications. JAMA 288,
Pharmacologyonline 1, 1–10 (2010). 16 Ceriello A, Esposito K, Piconi L et al. 2579–2588 (2002).
Oscillating glucose is more deleterious to
4 Bogdanov V Y, Osterud B. Cardiovascular 28 Atkinson MA, Eisenbarth GS. Type 1
endothelial function and oxidative stress than
complications of diabetes mellitus: the tissue diabetes; new perspective on disease
mean glucose in normal and Type 2 diabetic
factor perspective. Thromb. Res. 125(2), pathogenesis and treatment. Lancet 358,
patients. Diabetes 57(5), 1349–1354 (2008).
112–118 (2010). 221–229 (2000).
17 Fujisawa T, Ikegami H, Kawaguchi Y et al.
5 Gregoratos G. Leung G. Diabetes mellitus 29 American Diabetes Association. Standards of
Meta-analysis of association of insertion/
and cardiovascular disease in the elderly. Medical Care in Diabetes. Diabetes Care 35(1),
deletion polymorphism of angiotensin
In: Cardiovascular Disease In The Elderly S11–S63 (2012).
I-converting enzyme gene with diabetic
(4th Edition) Aronow WS, Flag JL, Rich MW nephropathy and retinopathy. Diabetologia nn Provides a quick and easy access to any
(Eds). Informa Health Care, NY, USA, 41(1), 47–53 (1998). needed piece of information regarding
190–220 (2008). diabetes and antidiabetic drugs.
18 Odawara M, Matsunuma A, Yamashita K.
6 Ceriello AD, Jamie H, Markolf L et al. Avoidance of mistyping of angiotensin- 30 Giaccari A, Giorda C B, Riccardi G, et al.
Postprandial hyperglycemia and converting enzyme gene polymorphism and its Evaluation of guidelines on diabetes
cardiovascular complications of diabetes: an association with diabetic complications. medication. Ann. Intern. Med. 156(10),
update. The International Prandial Glucose Nucleic Acids Symp. Ser. 23, 261–262 (1996). 752–753 (2012).
Regulation PGR Study Group. Nutr. Metab.
19 American Diabetes Association. Nutrition 31 Willett LR. Meta-analysis: self-monitoring in
Cardiovasc. Dis. 16(7), 453–456 (2006).
recommendations and interventions for non-insulin-treated Type 2 diabetes improved
7 Fox, CS, Coady S, Sorlie P D et al. Trends in diabetes: a position statement of the American HbA1c by 0.25%. Ann. Intern. Med. 156(12),
cardiovascular complications of diabetes. Diabetes Association. Diabetes Care JC6–JC12 (2012).
JAMA 292(20), 2495–2499 (2004). 31(Suppl. 1), S61–S78 (2008). 32 Mehanna AS. Insulin and oral antidiabetic
8 Przewlocka KM, Kosmala W, Mazurek W. 20 Dehghan M, Mente A, Teo KK et al. agents. Am. J. Pharm. Educ. 69(5), 1–119
Cardiovascular complications in diabetic Relationship between healthy diet and risk of (2005).
patients-pathogenesis, management and cardiovascular disease among patients on drug 33 Barnett AH, Bellary S. Inhaled human insulin
prevention. In: Focus On Diabetes Mellitus therapies for secondary prevention: a (Exubera): clinical profile and patient
Research. Ford AM (Ed.). Nova Science prospective cohort study of 31,546 high-risk considerations. Vasc. Health Risk Manag. 3(1),
Publishers, NY, USA, 6(1) 33–53 (2006). individuals from 40 countries. Circulation 83–91 (2007).
9 Sheetz MJ, King GL. Molecular 126(23), 2705–2712 (2012).
34 Zhou G, Sebhat IK, Zhang BB. Metformin
understanding of hyperglycemia’s adverse 21 Lopes SD, Paes de Miranda M. Physical and phenformin activate AMP-activated
effects for diabetic complications. JAMA 288, exercise on glycemic control in Type 1 diabetes protein kinase in the heart by increasing
2579–2588 (2002). mellitus. Nutr. Hosp. 26(3), 425–429 (2011). cytosolic AMP concentration. Acta Physiol.
10 Francia P, Cosentino F, Schiavoni M et al. 22 Balducci S, Zanuso S, Pugliese G, Church T, 196(1), 175–190 (2009).
p66Shc protein, oxidative stress, and Sigal RJ. Diet or diet plus physical activity in 35 Matschinsky FMN, Itzhak H, Oksana N.
cardiovascular complications of diabetes: the patients with early Type 2 diabetes. Lancet et al. Effects of a glucokinase activator on
missing link. J. Mol. Med. 87(9), 885–891 378(9809), 2066–2067 (2011). hepatic intermediary metabolism: study with
(2009).
23 Andrews RC, Cooper AR, Montgomery AA 13C-isotopomer-based metabolomics.
11 Desai KM, Chang T, Wang H et al. et al. Diet or diet plus physical activity versus Biochem. J. 444(3), 537–551 (2012).
Oxidative stress and aging: is methylglyoxal usual care in patients with newly diagnosed 36 Derosa G, Maffioli P. Peroxisome proliferator-
the hidden enemy? Can. J. Physiol. Pharmacol. Type 2 diabetes: the Early ACTID randomized activated receptor agonists on glycemic
88(3), controlled trial. Lancet 378(9786), 129–139 control, lipid profile and cardiovascular risk.
273–284 (2010). (2011). Curr. Mol. Pharmacol. 5, 272–281 (2012).
12 Schnell O, Stalleicken D, Daiber A, Marx N. 24 Mekary RA, Rimm EB, Giovannucci E, et al. 37 Ernest A, Abdu A, Mohamed YH, Kornelia T,
Endothelial function and oxidative stress in Eating patterns and Type 2 diabetes risk in Huba K. Medicinal chemistry and actions of
diabetes: active profile of the long-acting men: breakfast omission, eating frequency, and dual and pan PPAR modulators. Open Med.
nitrate pentaerythritol tetranitrate (PETN). snacking1–4. Am. J. Clin. Nutr. 94, 1525–1532 Chem. J. 5(Suppl. 2), 93–98 (2011).
Clin. Res. Cardiol. Suppl. 5(1), 35–41 (2010). (2011).

future science group www.future-science.com 427

Perspective | Mehanna
38 Jain AK, Vaidya A, Ravichandran V, Kashaw mellitus: guidance from studies of liraglutide. 3,7-dihydropurine-2,6-dione (BI 1356), a
SK, Agrawal RK. Recent developments and Diabetes Obes. Metab. 14(4), 304–314 (2012). highly potent, selective, long-acting, and orally
biological activities of thiazolidinone 51 Gough SC. Liraglutide: from clinical trials to bioavailable DPP-4 inhibitor for the treatment
derivatives: a review. Bioorg. Med. Chem. clinical practice. Diabetes Obes. Metab. 14(2), of Type 2 diabetes. J. Med. Chem. 50(26),
20(11), 3378–3395 (2012). 33–40 (2012). 6450–6453 (2007).
39 Holst JJ, Orskov C, Nielson OV et al. n Comprehensive review for liraglutide efficacy, 64 Blech S, Ludwig-Schwellinger E, Crafe-Mody
Truncated glucagon-like peptide I, an insulin EU et al. The metabolism and disposition of
safety, tolerability and place in therapy.
releasing hormone from the distal gut. FEBS the oral dipeptidyl peptidase-4 inhibitor,
Lett. 211, 169–174 (1987). 52 Manash PB, Kalra S. The novel use of GLP-1 Linagliptin, in humans. Drug Metab. Dispos.
analogue and insulin combination in Type 2 38, 667–678 (2010).
40 Perley MJ, Kipnis DM. Plasma insulin
diabetes mellitus. Recent Pat. Endocr. Metab.
responses to oral and intravenous glucose 65 Neumiller J. Pharmacolgy, efficacy, and safety
Immune Drug Discov. 6(2), 129–135 (2012).
studies in normal and diabetic subjects. J. Clin. of Linagliptin for the treatment of Type 2
Invest. 46, 1954–1962 (1967). 53 Ahren B. Inhibition of dipeptidy peptidase-4 diabetes. Ann. Pharmacother. 46(3), 358–367
(DPP-4): a target to treat Type 2 diabetes. (2012).
41 Dupre J, Ross S, Watson D et al. Stimulation
Curr. Enzym. Inhib. 7, 205–217 (2011).
of insulin secretion by gastric inhibitory 66 Neumiller JJ, Setter SM. Review of
polypeptide in man. J. Clin. Endocrinol. Metab. 54 Havale SH, Pal M. Medicinal chemistry Linagliptin for the treatment of Type 2
37, 826–828 (1973). approaches to the inhibition of dipeptidyl diabetes mellitus. Clin. Ther. 34(5), 993–1005
peptidase-4 for the treatment of Type 2 (2012).
42 Zettl H, Schubert-Zsilavecz M, Steinhhilber
diabetes. Bioorg. Med Chem. 17(5), 1783–1802
D. Medicinal chemistry of incretin mimetics 67 Tahrani AA, Piya M, Barnett AH. Drug
(2009).
and DPP-4 inhibitors. ChemMedChem. 5, evaluation. Vildagliptin-metformin single-
179–185 (2010). 55 Gwaltney S L. Medicinal chemistry approaches tablet combination. Advances Therapeutics
to the inhibition of dipeptidyl peptidase IV. 26(2), 138–154 (2009).
nn Provides the most comprehensive and correct Curr. Top. Med. Chem. 8(17), 1545–1552
information for GLP-1 structure and DPP-IV 68 Feng J, Zhang Z, Wallace MB et al. Discovery
(2008).
inhibitors structure–activity relationship. of alogliptin; a potent, selective, bioavailable,
56 Bhapkar R, Ganu G, Garud A, Kshirsagar A. and efficacious inhibitor of dipeptidyl
43 Hui H, Zhao X, Perfetti R. Structure and Novel approach of management of diabetes peptidase. J. Med. Chem. 50(10), 2297–2300
function studies of glucagon-like peptide-1 mellitus with DPP-IV inhibitors and incretins. (2007).
(GLP-1): the designing of a novel Pharma. Science Monitor 3, 48–58 (2012).
pharmacological agent for the treatment of 69 Russell-Jones D, Gough S. Recent advances in
57 Thornberry NA, Weber AE. Discovery of incretin-based therapies. Clin. Endocrinol.
diabetes. Diabetes Metab. Res. Rev. 21, 313–331
Januvia (sitagliptin), a selective dipeptidyl 77(4), 489–499 (2012).
(2005).
peptidase IV inhibitor for the treatment of
44 Deacon C, Knudsen LB, Madsen K, Wiberg 70 Cooper GJ, Willis AC, Clark A, Turner RC,
Type 2 diabetes. Curr. Top. Med. Chem. 7(6),
FC, Jacobsen O, Holst JJ. Dipeptidyl peptidase Sim RB, Reid KB. Purification and
557–568 (2007).
IV resistant analogs of glucagon-like peptide- characterization of a peptide from amyloid-
58 Engel SS , Williams-Herman DE, Golm GT rich pancreases of Type 2 diabetic patients.
1which have extended metabolic stability and
et al. Sitagliptin: review of preclinical and Proc. Natl Acad. Sci. USA 8(23), 8628–8632
improved biological activity. Diabetologia
clinical data regarding incidence of (1987).
41(3), 271–278 (1998).
pancreatitis. Int. J. Clin. Pract. 64(7), 984–990
45 Furman BL. The development of Byetta 71 Ryan GJ, Jobe LJ, Martin R. Pramlintide in
(2010).
(exenatide) from the venom of the Gila the treatment of Type 1 and Type 2 diabetes
59 Augeri D, Robl J, Betebenner D et al. mellitus. Clin. Ther. 27, 1500–1512 (2005).
monster as an antidiabetic agent. Toxicon.
Discovery and preclinical profile of saxagliptin
59(4), 464–471 (2012). 72 Sasahara K, Hall D, Hamada D. Effect of lipid
(BMS-477118): a highly potent, long-acting,
46 Buse JB, Henr R, Han J et al. Effects of type on the binding of lipid vesicles to IAPP
orally active dipeptidyl peptidase IV inhibitor
exenatide (exendin-4) on glycemic control over amyloid fibrils. Biochemistry 49, 3040–3048
for the treatment of Type 2 diabetes. J. Med.
30 weeks in sulfonylurea-treated patients with (2010).
Chem. 48, 5025–5037 (2005).
Type 2 diabetes. Diabetes Care 27, 2628–2635 73 Nilsson MR, Nguyen LL, Raleigh DP.
60 Waugh N, Cummins E, Royle P et al. Newer
(2004). Synthesis and purification of amyloidogenic
agents for blood glucose control in Type 2
47 Faludi P, Brodows R, Burger J, Ivanyi T, Braun peptides. Anal. Biochem. 288(1), 76–82
diabetes: systematic review and economic
DK. The effect of exenatide re-exposure on (2001).
evaluation. Health Technol. Assess. 14(36),
safety and efficacy. Peptides 30(9), 1771–1774 1–248 (2010). 74 Adeghate E, Kalasz H. Amylin analogues in
(2009). the treatment of diabetes mellitus: medicinal
61 Yang LP. Saxagliptin: a review of its use as
48 Arulmozhi DK. Portha B. GLP-I based therapy chemistry and structural basis of its function.
combination therapy in the management of
for Type 2 diabetes. Eur. J. Pharm. Sci. 28, Open Med. Chem. J. 5, 78–81 (2011).
Type 2 diabetes mellitus in the EU. Drugs
96–108 (2006). 72(2), 229–248 (2012). n Although very short, delivers a lot of
49 Lotfy M, Singh J, Kalasz H , Tekes K, 62 Haiyan Li, Li Y, Conrad KP, Tou GP, June ZS. information about native amylin structure,
Adeghate E. Medicinal chemistry and Pharmacokinetic study of saxagliptin in its actions, metabolism and receptors.
applications of incretins and DPP-4 inhibitors healthy Chinese subjects. Clin. Drug Investig. 75 Nanga RP, Brender JR, Xu J, Veglia G.
in the treatment of Type 2 diabetes mellitus. 32(7), 465–473 (2012). Structures of rat and human islet amyloid
Open Med. Chem. J. 5, 82–92 (2011). polypeptide IAPP(I-19) in micelles by NMR
63 Eckhardt M, Langkopf E, Mark M et al.
50 Barnett AH. The role of GLP-1 mimetics and 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3- spectroscopy. Biochemistry 47(48),
basal insulin analogues in Type 2 diabetes methyl-1-(4-methyl-quinazolin-2-ylmethyl)- 12689–12697 (2008).

428 Future Med. Chem. (2013) 5(4) future science group

 Antidiabetic agents: past, present & future | Perspective
76 Ryan GJ, Jobe LJ, Martin R. Pramlintide in 90 de Laszlo SE, Hacker C, Li B et al. Potent, 104 Pereira LL, Pereira CA, de Souza SP, Santos
the treatment of Type 1 and Type 2 diabetes orally absorbed glucagon receptor antagonists. CD. Therapeutic action of white beans by
mellitus. Clin. Ther. 27(10), 1500–1512 Bioorg. Med. Chem. Lett. 9, 641–646 (1999). changing the digestion of carbohydrates.
(2005). 91 Duffy JL, Kirk BA, Konteatis Z et a1. J. Nat. Pharm. 3, 9–16 (2012).
77 Steve MH, Wilhelm K. Pramlintide in the Discovery and investigation of a novel class of 105 Etxeberria U, de la Garza AL, Campion J,
treatment of diabetes mellitus. BioDrugs 22(6), thiophene-derived antagonists of the human Martinez JA, Milagro FI. Antidiabetic
375–386 (2008). glucagon receptor. Bioorg. Med. Chem. Lett. 15, effects of natural plant extracts via
78 Riddle M, Frias J, Zhang B, et al. Pramlintide 1401–1405 (2005). inhibition of carbohydrate hydrolysis
improved glycemic control and reduced weight 92 Kurukulasuriya R, Sorensen B, Link J et al. enzymes with emphasis on pancreatic
in patients with Type 2 diabetes using basal Biaryl amide glucagon receptor antagonists. alpha amylase. Expert Opin. Ther. Targets
insulin. Diabetes Care 30(11), 2794–2799 Bioorg. Med. Chem. Lett. 14, 2047–2050 16(3), 269–297 (2012).
(2007). (2004). 106 Yoshikawa Y, Yasui H. Zinc complexes
79 Younk LM, Mikeladze M, Davis SN. 93 Ladouceur GH, Cook J, Hertzog D et al. developed as metallo-pharmaceutics for
Pramlintide and the treatment of diabetes: a Integration of optimized substituent patterns treating diabetes mellitus based on the bio-
review of the data since its introduction. Expert to produce highly potent 4-aryl-pyridine medicinal inorganic chemistry. Curr. Top.
Opin. Pharmacother. 12(9), 1439–1451 (2011). glucagon receptor antagonists. Bioorg. Med. Med. Chem. 12(3), 210–218 (2012).

n Provide information about pramlinitide Chem. Lett. 12, 3421–3424 (2002). 107 Thompson KH, Lichter J, LeBel C, Scaife
94 Liang R, Abrardo L, Brady E et al. Design and MC, McNeill JH, Orvig C. Vanadium
including chemistry, pharmacodynamics,
synthesis of conformationally constrained treatment of Type 2 diabetes: a view to the
pharmacokinetics, drug interaction and
tri-substituted ureas as potent antagonists of future. J. Inorg. Biochem. 103(4), 554–558
clinical efficacy.
the human glucagon receptor. Bioorg. Med. (2009).
80 Nain S, Bansal N. Antidiabetic drugs for the
Chem. Lett. 17, 587–592 (2007). 108 Coppari R, Bjorbaek C. Leptin revisited: its
treatment of diabetes: a review. Asian
95 Ling A, Hong Y, Gonzalez J et al. Identification mechanism of action and potential for
J. Biochem Pharm. Res. 2(2), 148–153 (2012).
of alkylidene hydrazides as glucagon receptor treating diabetes. Nat. Rev. Drug Discov.
81 Chao EC, Henry RR. SGLT2 inhibition: a 11(9), 692–708 (2012).
antagonists. J. Med. Chem. 44, 3141–3149
novel strategy for diabetes treatment. Nat. Rev.
(2001). 109 Kawasaki N, Tanimoto T, Tanaka A.
Drug Discov. 9(7), 551–559 (2010).
96 Pal M. Protein-tyrosine-phosphatase 1B Characterization of aldose reductase and
82 Ghosh RK, Ghosh SM, Chawla SC, aldehyde reductase from rat testis. Biochim.
inhibitors (PTB1BI). Curr. Med. Chem.
Jasdanwala SA. SGLT2 inhibitors: a new Biophys. Acta 996(1–2), 30–36 (1989).
16(29), 3858–3874 (2009).
emerging therapeutic class in the treatment of
97 Montalibet J, Kennedy BP. Therapeutic 110 Stribling D, Perkins C M. Aldose reductase
Type 2 diabetes mellitus. J. Clin. Pharmacol.
strategies for targeting PTBIB in diabetes. inhibitors. Rec. Adv. Diabetes 2, 169–176
52(4), 457–461 (2012).
Drug Discov. Today 2, 129–135 (2005). (1986).
83 Anderson SL, Marrs JC. Dapagliflozin for the
98 Rotella DP. Novel second-generation 111 Jaiswal N, Bhatia V, Srivastava SP, Srivastava
treatment of Type 2 diabetes Ann.
approaches for the control of Type 2 diabetes. AK, Tamrakar A. Antidiabetic effect of
Pharmacother. 46(4), 590–598 (2012).
J. Med. Chem. 47, 4111–4112 (2004). Eclipta alba associated with the inhibition of
84 Komala MG, Panchapakesan U, Pollock C, alpha-glucosidase and aldose reductase. Nat.
Mather A. Sodium glucose co-transporter 2 99 Hooft van Huijduijnen R, Bombrun A,
Prod. Res. 26(24), 2363–2367 (2012).
and the diabetic kidney. Curr. Opin. Nephrol. Swinnen D. Selecting protein tyrosine
phosphatases as drug targets. Drug Discov. 112 Ali S, Saeed A, Abbas N, Shahid M, Bolte M,
Hypertens. 22(1), 113–119 (2013).
Today 7, 1013–1019 (2002). Iqbal J. Design, synthesis and molecular
85 Paisley AJ, Yadav R, Younis N , Rao- modeling of novel methyl[4-oxo-2-
Balakrishna P, Soran H .Dapagliflozin: a 100 Chen ZH, Sun LP, Zhang W et al. Synthesis
(aroylimino)-3-(substituted phenyl)
review on efficacy, clinical effectiveness and and biological evaluation of heterocyclic ring-
thiazolidin-5-ylidene]acetates as potent and
safety. Expert Opin. Investig. Drugs 22(1), substituted chalcone derivatives as novel
selective aldose reductase inhibitors. Med.
131–140 (2013). inhibitors of protein tyrosine phosphatase 1B.
Chem. Comm. 3(11), 1428–1434 (2012).
Bull. Korean Chem. Soc. 33(5), 1505–1508
86 Kanwal A, Banerjee SK. SGLT inhibitors: a 113 Pegklidou K, Koukoulitsa C, Nicolaou I,
(2012).
novel target for diabetes. Pharm. Pat. Analyst Demopoulos V J. Design and synthesis of
2(1), 77–91 (2013). 101 Navarrete-Vazquez G, Ramirez-Martinez M,
novel series of pyrrole based chemotypes and
Estrada-Soto S et al. Synthesis, in vitro and
87 Yao CH, Song JS, Chen CT et al. Synthesis their evaluation as selective aldose reductase
in silico screening of ethyl 2-(6-substituted
and biological evaluation of novel inhibitors. A case of bioisosterism between a
benzo[d]thiazol-2-ylamino)-2-oxoacetates as
C-indolylxylosides as sodium-dependent carboxylic acid moiety and that of a tetrazole.
protein-tyrosine phosphatase 1B inhibitors.
glucose co-transporter 2 inhibitors. Bioorg. Med. Chem. 18(6), 2107–2114 (2010).
Eur. J. Med. Chem. 53, 346–355 (2012).
Eur. J. Med. Chem. 55, 32–38 (2012). 114 Vo T, Marcus KB. Ranirestat: a selective
102 Zhang S, Liu S, Tao R et al. A highly selective
88 Ling A, Plewe M, Gonzalez J et al. Human aldose reductase inhibitor for diabetic
and potent PTP-MEG2 inhibitor with
glucagon receptor antagonists based on sensorimotor polyneuropathy. J. Pharm
therapeutic potential for Type 2 diabetes.
alkylidene hydrazides. Bioorg. Med. Chem. Lett. Technol. 24(6), 340–344 (2008).
J. Am. Chem. Soc. 134(43), 18116–18124
12, 663–666 (2002). 115 Pal M. Medicinal chemistry approaches for
(2012).
89 Chang LL, Sidler K, Cascieri M et al. glucokinase activation to treat Type 2
103 Li WL, Jian C, Luo MH et al. Glycogen
Substituted imidazoles as glucagon receptor diabetes. Curr. Med. Chem. 16(29),
phosphorylase inhibitors. Curr. Enzym. Inhib.
antagonists. Bioorg. Med. Chem. Lett. 11, 3858–3874 (2009).
7(4), 259–267 (2011).
2549–2553 (2001).

future science group www.future-science.com 429

Perspective | Mehanna
116 Sayed S, Matschinsky FM, Stanley CA. 127 Baliga MS, Pai RJ, Bhat HP, Palatty PL, applications of pyrazolines. Expert Opin.
Hyperinsulinism due to activating mutations Boloor R. Chemistry and medicinal properties Ther. Pat. 22(3), 253–291 (2012).
of glucokinase. Front. Diabetes 21, 146–157 of the Bakul (Mimusops elengi Linn). Food Res. 136 Singh, AK, Sahu VK, Yadav D. Biological
(2012). Int. 44(7), 1823–1829 (2011). activities of 2,5-di-substituted-1,3,4-
117 Doliba NM, Qin W, Najafi H et al. 128 Kumar T, Chandrashekar KS, Bauhinia PL. A oxadiazoles. Int. J. Pharma. Sci. Res. 2(6),
Glucokinase activation repairs defective review of its ethnobotany, phytochemical and 135–147 (2011).
bioenergetics of islets of Langerhans isolated pharmacological profile. J. Med. Plant Res. 137 McCoull W, Addie MS, Birch AM et al.
from Type 2 diabetics. Am J. Physiol. 302(1), 5(4), 420–431 (2011). Identification, optimization and in vivo
E87–E102 (2012). 129 Madhava NM, Srinivas P. Edited by Awaad evaluation of oxadiazole DGAT-1 inhibitors
118 Matschinsky FM. Research and development AS, Singh VK, Govil JN, Butea ML. for the treatment of obesity and diabetes.
of glucokinase activators for diabetes therapy: Chemistry, medicinal properties and Bioorg. Med. Chem. Lett. 22(12), 3873–3878
theoretical and practical aspects. Handb. Exp. technological aspects. Recent Prog. Med. (2012).
Pharmacol. 203, 357–401 (2011). Plants 28, 363–385 (2010). 138 Birendra B, Rakesh Bachwani, Mukesh K,
119 Matschinsky FM, Zelent B, Doliba N et al. 130 Tooley JE, Waldron-Lynch F, Herold KC. Rakhi A, Jyoti S, Vandana S. Exploring
Glucokinase activators for diabetes therapy. New and future immunomodulatory therapy potential of 1, 2, 4-triazole: a brief review.
Diabetes Care 34(2), S236–S243 (2011). in Type 1 diabetes. Trends Mol. Med. 18(3), Pharmacol. Online Newslett. 1192–1222
173–181 (2012). (2011).
120 Papazafiropoulou AK, Kardara MS, Pappas
SI. Challenges for the treatment of diabetes n One of very few references focused on 139 Roy A, Bhanwase AS, Patil TD. Synthesis and
mellitus. Recent Pat. Endocr. Metab. Immune alternate therapy for Type 1 diabetes. Covers evaluation of some novel 5-[4-(substituted)
Drug Discov. 5(3), 203–209 (2011). potential techniques for future therapy of benzylidene]-2,4 thiazolidinediones as oral
antihyperglycemic agents. Res. J. Pharm. Biol.
121 Sarabu R, Bizzarro FT, Corbett WL et al. Type 1 diabetes.
Chem. Sci. 3(3), 452–464 (2012).
Discovery of piragliatin-first glucokinase 131 Karadimos MJ, Kapoor A, El Khattabi I,
activator studied in Type 2 diabetic patients. Sharma A. b-cell preservation and
J. Med. Chem. 55 (16), 7021–7036 (2012). regeneration for diabetes treatment: where are „„Patents
122 Hung HY, Qian K, Morris-N, SL, Hsu CS, we now? Diabetes Manag. 2(3), 213–222 201 Rosado L, Jorge L, Duarte Vazquez MA:
Lee KH. Recent discovery of plant-derived (2012). MX2011001866 A 20120829 (2012).
antidiabetic natural products. Nat. Prod. Rep. 132 Ruan Q, Wang T, Kameswaran V et al. The 202 Boehme T, Engel C, Guessregen S, Haack T,
9(5), 580–606 (2012). microRNA-21-PDCD4 axis prevents Type 1 Ritter K, Tschank G: WO 2012120055 A1
123 Brahmachari G. Promising antidiabetic diabetes by blocking pancreatic b cell death. 20120913 (2012).
agents of natural origin: an overview. Proc. Natl Acad. Sci. USA 108(29),
Indian J. Nat. Prod. Resour. 1(1–2), 17–22 12030–12035 (2012). „„Websites
(2005). 133 Sivakumar R, Pradeepchandran R, Jayaveera 301 WHO diabetes.
124 Calway T, Du GJ, Wang C Z, et al. Chemical K N, Kumarnallasivan P, Vijaianand P www.who.int/mediacentre/factsheets/fs312/
and pharmacological studies of Oplopanax R,Venkatnarayanan R. Benzimidazole: an en/index.html
horridus, a North American botanical. J. Nat. attractive pharmacophore in medicinal
302 American Diabetes Association. Diabetes
Med. 66(2), 249–256. 126 (2012). chemistry. Int. J. Pharm. Res. 3(3), 19–31
statistics.
(2011).
125 Singh J, Cumming E, Manoharan G, Kalasz www.diabetes.org/diabetes-basics/diabetes-
H, Adeghate E. Medicinal chemistry of the 134 Walia R , Hedaitullah MD, Naaz S F, Iqbal statistics/
antidiabetic effects of momordica charantia: K, Lamba H S. Benzimidazole derivatives an
303 Agency for Healthcare Research and Quality.
active constituents and modes of actions. overview. Int. J. Res. Pharm. Chem. 1(3),
Nutritional management of diabetes mellitus.
Open Med. Chem. J. 5, 70–77 (2011). 565–574 (2011).
www.guideline.gov/syntheses/synthesis.aspx?i
126 Parle M, Singh K. Musk melon is eat-must 135 Shaaban MR, Mayhoub AS, Farag AM. d=36617&search=diabetes#physical
melon. Int. Res. J. Pharm. 2(8), 52–57 (2011). Recent advances in the therapeutic

430 Future Med. Chem. (2013) 5(4) future science group