title: 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.
authors.affiliation: Agouron Pharmaceuticals, Inc., San Diego, California 92121, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Kaldor
authors.forename: V J
authors.initials: VJ
authors.lastname: Kalish
authors.forename: J F
authors.initials: JF
authors.lastname: Davies
authors.forename: B V
authors.initials: BV
authors.lastname: Shetty
authors.forename: J E
authors.initials: JE
authors.lastname: Fritz
authors.forename: K
authors.initials: K
authors.lastname: Appelt
authors.forename: J A
authors.initials: JA
authors.lastname: Burgess
authors.forename: K M
authors.initials: KM
authors.lastname: Campanale
authors.forename: N Y
authors.initials: NY
authors.lastname: Chirgadze
authors.forename: D K
authors.initials: DK
authors.lastname: Clawson
authors.forename: B A
authors.initials: BA
authors.lastname: Dressman
authors.forename: S D
authors.initials: SD
authors.lastname: Hatch
authors.forename: D A
authors.initials: DA
authors.lastname: Khalil
authors.forename: M B
authors.initials: MB
authors.lastname: Kosa
authors.forename: P P
authors.initials: PP
authors.lastname: Lubbehusen
authors.forename: M A
authors.initials: MA
authors.lastname: Muesing
authors.forename: A K
authors.initials: AK
authors.lastname: Patick
authors.forename: S H
authors.initials: SH
authors.lastname: Reich
authors.forename: K S
authors.initials: KS
authors.lastname: Su
authors.forename: J H
authors.initials: JH
authors.lastname: Tatlock
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002144:Callithrix; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D008252:Macaca fascicularis; D008297:Male; D019888:Nelfinavir / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D019888:Nelfinavir