title: L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: B D
authors.initials: BD
authors.lastname: Dorsey
authors.forename: R B
authors.initials: RB
authors.lastname: Levin
authors.forename: S L
authors.initials: SL
authors.lastname: McDaniel
authors.forename: J P
authors.initials: JP
authors.lastname: Vacca
authors.forename: J P
authors.initials: JP
authors.lastname: Guare
authors.forename: P L
authors.initials: PL
authors.lastname: Darke
authors.forename: J A
authors.initials: JA
authors.lastname: Zugay
authors.forename: E A
authors.initials: EA
authors.lastname: Emini
authors.forename: W A
authors.initials: WA
authors.lastname: Schleif
authors.forename: J C
authors.initials: JC
authors.lastname: Quintero
mesh_terms: 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
chemical_list: D017320:HIV Protease Inhibitors; D011725:Pyridines; D019469:Indinavir; D016333:HIV Protease