Pharmaceutical

Chemistry
Nayang A. Kgakatsi, PhD
Dept. of Pharmacy

Semester II, 2024

 What is a drug?
1. A substance used as a medication or in the preparation of medication

2. According to the Food, Drug, and Cosmetic Act: A substance recognized

in an official pharmacopoeia or formulary
3. A substance intended for use in the diagnosis, cure, mitigation, treatment,
or prevention of disease

4. A substance other than food intended to affect the structure or function

of the body

(Merriam –Webster Dictionary)

 What is a therapeutic drug?
 A chemical substance that when ingested, blocks, modulates or enhances a
biochemical or physiological process(es) for the purpose of treatment in
disease

 Drugs may be taken for short times (acute) or over long periods (chronic)
or may be taken to avoid or blunt a disease process (prophylactic).

 Drugs may be directed to affect human processes or may be directed

towards controlling pathogenic organisms such as bacterial, viral or parasitic
infections.
 The Value of Drugs
 Drugs improve quality of life, control or eradicate many debilitating diseases,
save and prolong countless lives and save $billions in hospital and medical
costs

For example:
 Peptic ulcers are now almost unheard of due to introduction of safe
controllers of stomach acid secretion, cytoprotective agents and
novel triple therapies using antibiotics.
 Activity 1
Give examples on how drugs improved the quality of life
Answers!
 Heart disease is controlled and quality life prolonged for millions due
to use of effective blood pressure control medicines and cholesterol
lowering agents (statins).

 Survival rates of many cancers have dramatically improved due to

introduction of novel (if expensive) therapies

 AIDs is now a chronic managed disease rather than a death sentence

 Hepatitis C infection can now be cured quickly and with few side
effects with a new generation of anti-viral super-drugs
 Making drugs is hard. But worth it!
Some notable quotes
“ We try to remember that medicine is for the patient. We try to never forget that medicine is for the people. It is
not for the profits. The profits will follow, and If we have remembered that, they have never failed to appear”
- George Merck, Medical College of Virginia, December 1950

“I never found it easy. People say I was lucky twice but I resent that. We stuck with [cimetidine] for four
years with no progress until we eventually succeeded. It was not luck, it was bloody hard work.”
[Rejecting that drug discovery was easier in the past.]
-Sir James Black- quoted in Financial Times 1 Feb, 2009

‘It’s harder to bring a new drug to market than to put a man on the moon’ Attributed to Chris Hall
accepting the Heroes of Chemistry Award from the ASC on behalf of Merck inventors of the AIDs drug
Isentress, ACS National Meeting 8 Sep. 2013
 UNMET MEDICAL
NEEDS
Learning goal
 Determine attributes of unmet medical needs
 Assess diseases as unmet needs

Vocabulary
 unmet medical need, orphan disease, rare disease, & neglected tropical
disease
Unmet Medical Needs

 Drug companies create drug programs around unmet medical needs.

 Medical needs are inadequately addressed diseases or health

concerns.
 Unmet needs have no existing therapy, or perhaps the existing therapy
is unsatisfactory for a certain part of the patient pool.
For Example
 Maybe the therapy doesn't work for certain patients.
 Implicit in the idea of an unmet medical need is that there is a need.
 There is a demand for the treatment
 So if a drug company can satisfy an unmet medical need, then patients will be
receptive to the treatment, and physicians will also prescribe the treatment to
their patients.
 The market size for an unmet medical need is important. Drug makers
are driven by profits, in part, and a larger market makes the
development of a drug more desirable.

 If a disease has a small population or small patient pool, it will be called

an orphan or rare disease -- if the disease has severe consequences.

 Some countries provide incentives for research on rare diseases – these

uncommon but severe diseases -- so that they are not ignored in the
research process.
  Let's see if some of these diseases on the screen qualify as an unmet
medical need.

1. Alzheimer's disease
 Beyond the early stages of the disease, Alzheimer's has no effective
drugs. Alzheimer's disease is a huge unmet medical need.

2.How about high blood pressure or hypertension?

 Many people have high blood pressure, so there is a large market. But, there
are also many drugs that treat hypertension.
 This list includes the ACE inhibitors, beta blockers, and calcium channel
blockers to name a few.
 Although many suffer from high blood pressure, hypertension is not
considered an unmet need.
3. Chagas disease
 Chagas disease is a parasitic infection that
can lead to congestive heart failure.

 Chagas disease is considered a neglected

tropical disease or NTD.

 NTDs affect tropical and subtropical regions

of the world.
 The World Health Organization or WHO maintains an NTD list, which
includes numerous infectious diseases and even conditions like
venomous snake bites.
 Chagas disease is an unmet need.
4. How about diabetes?
 While many diabetes drugs are on the market,
advanced diabetic patients require insulin
injections.
 Insulin injections are painful and pose
infection risks.
 An oral form of insulin would be of great
benefit to patients and is an unmet medical
need.
 So yes, if we could get oral insulin. So, even
diseases with existing treatments can
represent an unmet need.
 How to determine Unmet Medical Need
 To determine whether a disease is an unmet medical need, one
must research the conditions, available therapies, and possible gaps
and treatments.
 Drug companies must continuously research the health care field for
unmet medical needs.

 Through identifying unmet needs, a drug company increases the chance that
any new drug will provide both financial gain to the company and a health care
benefit to patients.
 Conclusion
 We have now learned the definition of an unmet medical need...
that is, a disease that cannot be satisfactorily treated with current
therapies or drugs.

 We've also assessed a number of different diseases to determine whether

those specific diseases themselves represent an unmet medical need.
 Pharma can react quickly to address a new medical need
Leading companies by number of COVID-19 drugs and
vaccines in development as of June 3, 2022

As of June 3, 2022, there were 1,521 drugs and vaccines in development targeting the coronavirus disease (COVID-19). American biotech company
Moderna was the second ranked company worldwide with 12 drugs/vaccines in development targeting COVID-19.
Revenue of the worldwide pharmaceutical
market continues to grow
Total global pharmaceutical research and development (R&D)
spending also growing (2012 to 2026)
 Global pharmaceutical sales from 2017 to 2021, by
region (US is by far largest)

https://www.astrazeneca.com/content/dam/az/Investor_Relations/annual- report-2021/pdf/AstraZeneca_AR_2021.pdf
And most new drugs are first approved in the US
 TARGETS, ASSAYS, &
LEADS
Learning goal
 How to prioritize a drug target
 Describe role of an assay
 Summarize lead selection

Vocabulary
Drug target, downstream, druggable, target-based drug discovery, assay,
potency, efficacy, screening, hit, & lead
 Once we have identified our unmet medical need, it's now time to begin
the drug discovery process.
 So, this beginning starts with unraveling the biological pathways that are
associated with the disease.
 Biological pathways are managed by proteins for the most part --
enzymes and receptors.

 And in theory, if you can block the action of an enzyme or receptor along
a pathway, you can potentially have a therapeutic effect on a disease.
 We have a hypothetical set of enzymes and
receptors -- potential drug targets,
associated with different responses.
Receptor A pain response
 Our interest is on inflammation
response Enzyme B Enzyme C
inflammation
 As we look at this pathway, we have five response

different potential targets on the screen Receptor D Enzyme E

clotting
in our rectangles and ovals. response

 One of these compounds, one of these

proteins, will be our drug target.
So how do we select a target?
 Well, proteins connected to just one
response pathway are preferred. Receptor A pain response

 Of the targets on the screen, Enzyme B and

Enzyme B Enzyme C
Enzyme C are linked to just the inflammation
response
inflammation pathway.
Receptor D Enzyme E
 These would be the most attractive targets. clotting
response

 In general, the proteins closer to the

response are more favorable.
 These are said to be more downstream
rather than, on the left, upstream.
 Therefore, Enzyme C would be more downstream than Enzyme B and
would be the top pick.

 The molecular biology team would study Enzyme C to determine

whether it is druggable, which means it's able to be affected by the
action of a drug.
 Selecting a target is a key step in a target-based, drug discovery
program, which is the most common type of program for discovering
orally delivered drugs.
 After target selection, the biology team will need to create a
biochemical test that measures the activity of the target protein.
 This test is called an assay.
 This test, or assay, determines two (2) things;

1. It allows quantification of a molecule's potency, or the drug

concentration required to act on the target protein.
2. The assay also measures a molecule's efficacy, or the
magnitude of the effect, the drug's influence, on the target.
 With an assay in hand, the discovery team will test the potency
and efficacy of a large number of molecules against the selected
target. This is the screening campaign.
 During a screening campaign, potentially over a million molecules
may be tested.
 Screening campaigns are often automated to increase
speed and reproducibility.
 At the end of the campaign, the discovery team will have
potency and efficacy data on all the screened molecules.
 The most promising compounds are called hits.
 A screening campaign may give hundreds or even thousands of
hits.
 The very best hits will be promoted to lead status.
 A program may have multiple leads but normally just one will
be promoted to the status of primary lead and advance for
further research.
 The other leads will be held in reserve as needed.
 Conclusion
We learned about, really, three key processes.
1. Drug targets, how these are the point of intervention
to affect a disease.
2. Assays. These are biochemical tests that are
developed to see whether we can affect that target.
3. Screening, use this assay to screen molecules so we
can find our compound of interest, our lead
compound, to advance in the drug discovery process.
 LEAD OPTIMIZATION
AND TOXICOLOGY
Learning goals
 List lead optimization factors
 Describe role of animal testing

Vocabulary
Lead optimization, pharmacokinetics, animal
model, toxicology & good laboratory practice
 We'll focus on the different factors that are relevant for improving or
optimizing the activity of a lead, and then we'll discuss how animal
studies are so important for predicting the activity that a molecule
may show in humans.

 Once a lead has been selected, the medicinal chemistry team will
begin to modify the structure of that lead molecule in order to
improve its properties.
 What properties will be optimized?
Four properties for lead optimization

 Potency
 Efficacy
 Toxicity
 Pharmacokinetics
Potency
 It indicates the amount or dosage of a drug
needed to produce a specific effect.
 Hits and leads are fairly potent, meaning they affect
the drug at a somewhat low concentration.

 During lead optimization, chemists will try to

improve potency so that you can decrease the dose
of the drug.

 Low-dose drugs tend to be safer.

 Potency is distinct from efficacy, which is about the drug's
ability to produce the desired therapeutic effect.

 When discussing drug potency, it often relates to the dose-

response relationship—the relationship between the amount of
a drug given and its effect on the body.

 A highly potent drug requires a lower dose to achieve a

therapeutic effect compared to a less potent one.

 Potency is expressed in terms of the drug's concentration,

typically measured in milligrams or micrograms.
Efficacy
 Which is related to the magnitude of a drug's effect, a
magnitude of how the drug affects the target protein.
 It is a measure of how well the drug performs in
terms of its intended purpose, such as treating a
medical condition, relieving symptoms, or preventing
disease progression.

Toxicity
 Potential toxic interactions of a lead will be
minimized.
 So the goal in lead optimization is to
minimize toxicity.
Pharmacokinetics
 Pharmacokinetics addresses how a drug
flows through the body.
 So a drug has to enter the body and leave
the body, and pharmacokinetics addresses
this idea.
 One of the outcomes of pharmacokinetics
is something like the drug's half-life.

 Lead optimization requires balancing these different properties with many

likely trade-offs. For example, reducing toxicity may require a slight loss in
potency.
 Animal Testing
 Promising leads are tested in animals.
 They're tested for their efficacy, toxicity, and
pharmacokinetics.
 Insight into how a molecule behaves in animals
is helpful for predicting how the same molecule
will behave in humans.
 Testing efficacy in animals requires an animal model of the disease.
Some diseases, like obesity, are easier to study in animals.
 Animal models for other diseases, like dementia or
depression, are much more difficult.
 Once a lead has been optimized to show promising
efficacy, toxicity, and pharmacokinetics in animals, the lead
will undergo toxicology testing in animals.

 Toxicology testing of a lead in animals is the immediate

precursor to human trials.
 Toxicology testing of a lead in animals is the
immediate precursor to human trials.
 A safe molecule in animals will likely be safe in
humans. To ensure consistent results, animal
toxicology tests follow standardized protocols called
good laboratory practice or GLP
 GLP toxicology studies are a regulatory
requirement for initiation of human trials.
 Conclusion
 So we've seen now the different types of activity of a molecule that are
monitored during lead optimization, whether it's efficacy or potency or
toxicity or pharmacokinetics, and then how animal studies further help
inform the drug discovery team about both the safety and efficacy of the
lead.
 CLINICAL TRIALS AND
APPROVAL
Learning goals
 Summarize clinical trials
 Prioritize safety and efficacy

Vocabulary
Investigational new drug, clinical trials, health volunteer, adverse drug reaction,
patient, pivotal trial, standard of care, new drug application, new molecular
entity. & new chemical entity
 We'll learn about what happens at each stage of the different
clinical trials and how all the clinical trials collectively help
determine the safety and effectiveness of a potential drug.
 To test a lead in humans, a drug company must submit an
investigational new drug application, or IND, with the Food
and Drug Administration, the FDA.

 The IND application details the lead's pre-clinical data, including

evidence of efficacy, completed toxicology tests in animals, and
manufacturing information.
 If the FDA does not raise objections within 30 days, then
the company will initiate clinical trials.
 Clinical trials are safety and efficacy tests performed in
humans.

Phase 1.
 Phase 1 trials involve 25 to 75 health
volunteers
 Phase 1 test subjects do not have the
disease of interest.
 Phase 1 trials determine safe dosing levels.
 Researchers also learn about what type of side effects, more
properly called adverse drug reactions, or ADRs, the patients
might show during later trials.

 Phase 1 trials monitor safety, but signs of efficacy may also be

apparent even though the test subjects are healthy volunteers.

 For example, if a molecule lowers cholesterol then

researchers will monitor cholesterol levels for early signs of
efficacy.
Phase 2
 Phase 2 trials typically enroll several hundred --
hundreds of patients ( ̴ 100s)
 Phase 2 test subjects do have the condition treated by
the lead.
 Phase 2 trials begin measuring efficacy.

 Phase 2 trials are often subdivided.

1. Phase 2a explore a [broad] range of doses.

2. Phase 2b trials focus on a narrow dosing range to balance

efficacy and any adverse drug reactions
 Phase 2b trials are often called pivotal trials.
Phase 3
 Phase 3 trials enroll a large pool of patients, maybe a
thousand to three thousand.
 Again, these are patients, not healthy volunteers.

 Large numbers allow the measurement of efficacy in a range

of patients and test the performance of the drug candidate
against known treatments.

 Known treatments are called the standard of care.

 As with other phases, safety remains a concern.

 Once clinical trials have been completed, all the data -- pre-
clinical and clinical data -- will be collected into one large
application, the new drug application or NDA.
 The FDA reviews the entire dossier. If the data show the
candidate molecule to be safe and effective, then the
molecule will be approved.

 Approval in other countries requires separate filings

with other drug regulatory agencies (e.g. BOMRA)

 A new drug like those found in an oral capsule or

tablet is called a new molecular entity, or NME.
 Sometimes these are called new chemical entities, or NCEs.
New Drugs 2022
Small and medium sized companies are now
dominating NME discovery