L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor.
A series of HIV protease inhibitors possessing a hydroxylaminepentanamide transition state isostere have been developed. Incorporation of a basic amine into the backbone of the L-685,434 (2) series provided antiviral potency combined with a highly improved pharmacokinetic profile in animal models. Guided by molecular modeling and an X-ray crystal structure of the inhibited enzyme complex, we were able to design L-735,524. This compound is potent and competitively inhibits HIV-1 PR and HIV-2 PR with Ki values of 0.52 and 3.3 nM, respectively. It also stops the spread of the HIV-1IIIb-infected MT4 lymphoid cells at concentrations of 25-50 nM. To date, numerous HIV-PR inhibitors have been reported, but few have been studied in humans because they lack acceptable oral bioavailability. L-735,524 is orally bioavailable in three animals models, using clinically acceptable formulations, and is currently in phase II human clinical trials.
Dorsey
B D
BD
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.
Levin
R B
RB
McDaniel
S L
SL
Vacca
J P
JP
Guare
J P
JP
Darke
P L
PL
Zugay
J A
JA
Emini
E A
EA
Schleif
W A
WA
Quintero
J C
JC
D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D004285:Dogs; D015195:Drug Design; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D015498:HIV-2 / Q000201:enzymology; D006801:Humans; D019469:Indinavir; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013601:T-Lymphocytes / Q000821:virology
D017320:HIV Protease Inhibitors; D011725:Pyridines; D019469:Indinavir; D016333:HIV Protease