Viracept (nelfinavir mesylate, AG1343): a potent, orally bioavailable inhibitor of HIV-1 protease.
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.
Kaldor
S W
SW
Agouron Pharmaceuticals, Inc., San Diego, California 92121, USA.
Kalish
V J
VJ
Davies
J F
JF
Shetty
B V
BV
Fritz
J E
JE
Appelt
K
K
Burgess
J A
JA
Campanale
K M
KM
Chirgadze
N Y
NY
Clawson
D K
DK
Dressman
B A
BA
Hatch
S D
SD
Khalil
D A
DA
Kosa
M B
MB
Lubbehusen
P P
PP
Muesing
M A
MA
Patick
A K
AK
Reich
S H
SH
Su
K S
KS
Tatlock
J H
JH
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
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D019888:Nelfinavir