Viracept (Nelfinavir Mesylate, AG1343):  A Potent, Orally Bioavailable Inhibitor of HIV-1 Protease

Abstract

Using a combination of iterative structure-based design and an analysis of oral pharmacokinetics and antiviral activity, AG1343 (Viracept, nelfinavir mesylate), a nonpeptidic inhibitor of HIV-1 protease, was identified. AG1343 is a potent enzyme inhibitor (Ki = 2 nM) and antiviral agent (HIV-1 ED50 = 14 nM). An X-ray cocrystal structure of the enzyme-AG1343 complex reveals how the novel thiophenyl ether and phenol-amide substituents of the inhibitor interact with the S1 and S2 subsites of HIV-1 protease, respectively. In vivo studies indicate that AG1343 is well absorbed orally in a variety of species and possesses favorable pharmacokinetic properties in humans. AG1343 (Viracept) has recently been approved for marketing for the treatment of AIDS.

Cadd: Pharmacological Approaches in Drug Design and Drug Discovery

“…Recent examples of molecules to which this approach has been applied include HIV-1 protease and the cholecystokinin-a receptor. [4] Computer-aided drug design, often called structure based drug design involves using the biochemical information of ligand-receptor interaction in order to postulate ligand refinements. F Indeed, using the crystal structure of the complex we can target regions of the ligand that fit poorly within the active site and postulate chemical modifications that lower the energetic potential by making more negative Vander Waals terms, thus improving complementarity with the receptor.…”

Chlorophenols in organic synthesis

“…The number of arylsulphides showed potential clinical application, for example, for the treatment of Alzheimer's disease and Parkinson's disease, for the treatment of asthma and obstructive lung diseases, for the treatment of human immunodeficiency virus (HIV) [39][40][41][42][43][44].…”

Use of Animal Models for Anti-HIV Drug Development

“…Investigators also developed drugs to the other HIV-1 enzymes: protease and integrase. While many of the protease inhibitors had poor efficacy against SIV, their pharmacokinetics could be assessed in animals, such as that of nelfinavir (Kaldor et al, 1997). Many integrase inhibitors were screened by Merck, leading to testing of many potential new compounds for good bioavailability in nonhuman primates and mice Pace et al, 2007).…”