Viracept (Nelfinavir Mesylate, AG1343): A Potent, Orally Bioavailable Inhibitor of HIV-1 Protease
- 1 November 1997
- journal article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 40 (24), 3979-3985
- https://doi.org/10.1021/jm9704098
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.Keywords
This publication has 6 references indexed in Scilit:
- Structure-Based Design and Synthesis of Substituted 2-Butanols as Nonpeptidic Inhibitors of HIV Protease: Secondary Amide SeriesJournal of Medicinal Chemistry, 1996
- Bis Tertiary Amide Inhibitors of the HIV-1 Protease Generated via Protein Structure-Based Iterative DesignJournal of Medicinal Chemistry, 1996
- Protein structure-based design of potent orally bioavailable, nonpeptide inhibitors of human immunodeficiency virus protease.Proceedings of the National Academy of Sciences of the United States of America, 1995
- Structure-based drug design of nonpeptidic P2 substituents for HIV-1 protease inhibitorsBioorganic & Medicinal Chemistry Letters, 1995
- New dipeptide isosteres useful for the inhibition of HIV-1 proteaseBioorganic & Medicinal Chemistry Letters, 1994
- Role of agostic interaction in .beta.-elimination of palladium and nickel complexes. An ab initio MO studyJournal of the American Chemical Society, 1985