Amprenavir (original brand name Agenerase,

GlaxoSmithKline GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the ten ...

) is a protease inhibitor used to treat

HIV infection Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ma ...

. It was approved by the

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

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 mg, delivered in 8 (eight) very large 150 mg gel capsules or 24 (twenty-four) 50 mg gel capsules twice daily. It was patented in 1992 and approved for medical use in 1999. Production of amprenavir was discontinued by the manufacturer on December 31, 2004; a

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

version (

fosamprenavir Fosamprenavir, sold under the brand names Lexiva and Telzir, is a medication used to treat HIV/AIDS. It is a prodrug of the protease inhibitor (pharmacology), protease inhibitor and antiretroviral drug amprenavir. It is marketed by ViiV Healthcare ...

), is available.

Background

Research aimed at development of

renin inhibitors Renin inhibitors are pharmaceutical drugs inhibiting the activity of renin that is responsible for hydrolyzing angiotensinogen to angiotensin I, which in turn reduces the formation of angiotensin II that facilitates blood pressure. Renin inhib ...

as potential

antihypertensive agents Antihypertensives are a class of drugs that are used to treat hypertension (high blood pressure). Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke and myocardial infarction. Evidence suggests tha ...

had led to the discovery of compounds that blocked the action of this peptide cleaving enzyme. The amino acid sequence cleaved by

renin Renin (etymology and pronunciation), also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin–angiotensin–aldosterone system (RAAS)—also known as the r ...

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 Protease inhibitors (PIs) are medications that act by interfering with protease, enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS and hepatitis C. These protease inhibitors prevent viral ...

. Incorporation of an

amino alcohol In organic chemistry, alkanolamines are organic compounds that contain both hydroxyl () and amino (, , and ) functional groups on an alkane backbone. The term alkanolamine is a broad class term that is sometimes used as a subclassification. Meth ...

moiety proved crucial to inhibitory activity for many of these agents. This unit is closely related to the one found in the

statine Statine is a gamma amino acid that occurs twice in the sequence of pepstatin, a protease inhibitor that is active against pepsin and other acid proteases. It is thought to be responsible for the inhibitory activity of pepstatin because it mimics ...

, an unusual amino acid that forms part of the

pepstatin Pepstatin is a potent inhibitor of aspartyl proteases. It is a hexa-peptide containing the unusual amino acid statine (Sta, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid), having the sequence Isovaleryl-Val-Val-Sta-Ala-Sta (Iva-Val-Val-Sta-Al ...

, a fermentation product that inhibits protease enzymes.

References

External links

Amprenavir bound to proteins
in the

Protein Data Bank The Protein Data Bank (PDB) is a database for the three-dimensional structural data of large biological molecules, such as proteins and nucleic acids. The data, typically obtained by X-ray crystallography, NMR spectroscopy, or, increasingly, cry ...

Abandoned drugs Carbamates CYP3A4 inhibitors HIV protease inhibitors Sulfonamides Tetrahydrofurans 1992 in science {{Antimicrobial-stub