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Amprenavir: Difference between revisions

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{{Short description|Chemical compound}}
{{Refimprove|date=December 2009}}
 
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| Drugs.com = {{drugs.com|monograph|amprenavir}}
| MedlinePlus = a699051
| licence_EU = Ageneraseyes
| licence_US = Amprenavir
| pregnancy_US = C
| pregnancy_category =
| legal_status = ℞Rx-only
| routes_of_administration = Oral ([[Capsule (pharmacy)|capsules]])
 
<!--Pharmacokinetic data-->
| bioavailability =
| protein_bound = 90%
| metabolism = hepatic[[Liver|Hepatic]]
| elimination_half-life = 7.1-101–10.6 hours
| excretion = <3% renal
 
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| ATC_prefix = J05
| ATC_suffix = AE05
| ATC_supplemental =
| PubChem = 65016
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
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| N=3 | O=6
| S=1
| molecular_weight = 505.628 g/mol
| smiles = O=C(O[C@H]1CCOC1)N[C@@H](Cc2ccccc2)[C@H](O)CN(CC(C)C)S(=O)(=O)c3ccc(N)cc3
| InChI = 1/C25H35N3O6S/c1-18(2)15-28(35(31,32)22-10-8-20(26)9-11-22)16-24(29)23(14-19-6-4-3-5-7-19)27-25(30)34-21-12-13-33-17-21/h3-11,18,21,23-24,29H,12-17,26H2,1-2H3,(H,27,30)/t21-,23-,24+/m0/s1
| InChIKey = YMARZQAQMVYCKC-OEMFJLHTBO
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C25H35N3O6S/c1-18(2)15-28(35(31,32)22-10-8-20(26)9-11-22)16-24(29)23(14-19-6-4-3-5-7-19)27-25(30)34-21-12-13-33-17-21/h3-11,18,21,23-24,29H,12-17,26H2,1-2H3,(H,27,30)/t21-,23-,24+/m0/s1
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}}
 
'''Amprenavir''' (original brand name '''Agenerase''', [[GlaxoSmithKline]]) is a [[protease inhibitor (pharmacology)|protease inhibitor]] used to treat [[HIV]] infection]]. It was approved by the [[Food and Drug Administration]] on April 15, 1999, for twice-a-day dosing instead of needing to be taken every eight hours. The convenient dosing came at a price, as the dose required is 1,200&nbsp;mg, delivered in 8 (eight) very large 150 mg gel capsules or 24 (twenty-four) 50 mg gel capsules twice daily.<ref name = "PI">{{cite web|title=Agenerase (amprenavir) Capsules. Full Prescribing Information. Section Dosage and Administration|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2002/21007s11,21039s10lbl.pdf|website=US Food and Drug Administration (http://www.fda.gov)|publisher=GlaxoSmithKline and Vertex Pharmaceuticals Inc.|accessdateaccess-date=29 November 2015}}</ref>
 
<!-- Society and culture -->
Production of amprenavir was discontinued by the manufacturer on December 31, 2004; a [[prodrug]] version ([[fosamprenavir]], brand name '''Telzir'''/'''Lexiva''') is available.
It was patented in 1992 and approved for medical use in 1999.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=509 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA509 |language=en}}</ref> Production of amprenavir was discontinued by the manufacturer on December 31, 2004; a [[prodrug]] version ([[fosamprenavir]]), is available.
 
[[File:3nu3 478.png|thumb|HIV-1 Protease dimer with Amprenavir (sticks) bound in the active site. PDB entry {{PDBe|3nu3}} <ref>{{Cite journal
| last1 = Shen | first1 = C. H.
| last2 = Wang | first2 = Y. F.
| last3 = Kovalevsky | first3 = A. Y.
| last4 = Harrison | first4 = R. W.
| last5 = Weber | first5 = I. T.
| title = Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters
| doi = 10.1111/j.1742-4658.2010.07771.x
| journal = FEBS Journal
| volume = 277
| issue = 18
| pages = 3699–3714
| year = 2010
| pmid = 20695887
| pmc =2975871
}}</ref>]]
 
==Background==
[[File:3nu3 478.png|thumb|left|[[HIV-1 protease]] dimer with amprenavir (sticks) bound in the active site. PDB entry {{PDBe|3nu3}}<ref>{{cite journal | vauthors = Shen CH, Wang YF, Kovalevsky AY, Harrison RW, Weber IT | title = Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters | journal = The FEBS Journal | volume = 277 | issue = 18 | pages = 3699–714 | date = September 2010 | pmid = 20695887 | pmc = 2975871 | doi = 10.1111/j.1742-4658.2010.07771.x }}</ref>]]
Research aimed at development of [[renin inhibitors]] as potential [[antihypertensive agents]] had led to the discovery of compounds that blocked the action of this peptide cleaving enzyme. The amino acid sequence cleaved by [[renin]] was found to be fortuitously the same as that required to produce the HIV peptide coat. Structure–activity studies on renin inhibitors proved to be of great value for developing [[HIV protease inhibitors]]. Incorporation of an [[amino alcohol]] moiety proved crucial to inhibitory activity for many of these agents. This unit is closely related to the one found in the [[statine]], an unusual amino acid that forms part of the [[pepstatin]], a fermentation product that inhibits protease enzymes.▼
 
▲Research aimed at development of [[renin inhibitors]] as potential [[antihypertensive agents]] had led to the discovery of compounds that blocked the action of this peptide cleaving enzyme. The amino acid sequence cleaved by [[renin]] was found to be fortuitously the same as that required to produce the HIV peptide coat. Structure–activity studies on renin inhibitors proved to be of great value for developing [[HIV protease inhibitors]]. Incorporation of an [[amino alcohol]] moiety proved crucial to inhibitory activity for many of these agents. This unit is closely related to the one found in the [[statine]], an unusual amino acid that forms part of the [[pepstatin]], a fermentation product that inhibits protease enzymes.{{cn|date=November 2022}}
==Synthesis==
{{clear|left}}
<ref>{{Cite journal | doi = 10.1021/jm00054a014| title = Discovery of a novel class of potent HIV-1 protease inhibitors containing the (R)-(hydroxyethyl)urea isostere| journal = Journal of Medicinal Chemistry| volume = 36| issue = 2| pages = 288| year = 1993| last1 = Getman | first1 = D. P. | last2 = Decrescenzo | first2 = G. A. | last3 = Heintz | first3 = R. M. | last4 = Reed | first4 = K. L. | last5 = Talley | first5 = J. J. | last6 = Bryant | first6 = M. L. | last7 = Clare | first7 = M. | last8 = Houseman | first8 = K. A. | last9 = Marr | first9 = J. J.
== References ==
}}</ref>
{{reflist}}▼
 
== External links ==▼
R.D. Tung, M.A. Murcko, G.R. Bhisetti, {{US Patent|5,558,397}} (1996). The scheme shown here is partly based on that used to prepare [[darunavir]] and [[fosamprenavir]] due to difficulty in deciphering the patent.
* [http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=478 Amprenavir bound to proteins] in the [[Protein Data Bank|PDB]]▼
 
==See also==
* [[Fosamprenavir]], a prodrug of amprenavir with improved pharmacokinetic parameters and dosing regimen
 
▲==External links==
▲* [http://www.ebi.ac.uk/pdbe-srv/PDBeXplore/ligand/?ligand=478 Amprenavir bound to proteins] in the [[Protein Data Bank|PDB]]
 
<br style="clear: both;" />
▲{{reflist}}
 
{{HIVpharm}}
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[[Category:Abandoned drugs]]
[[Category:Carbamates]]
[[Category:ProteaseCYP3A4 inhibitors]]
[[Category:HIV protease inhibitors]]
[[Category:Sulfonamides]]
[[Category:Tetrahydrofurans]]
[[Category:1992 in science]]
[[Category:Isobutyl compounds]]
[[Category:4-Aminophenyl compounds]]
 
{{Antimicrobial-stub}}
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