title: Identification of MK-944a: a second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors.
abstract: Recent results from human clinical trials have established the critical role of HIV protease inhibitors in the treatment of acquired immune-deficiency syndrome (AIDS). However, the emergence of viral resistance, demanding treatment protocols, and adverse side effects have exposed the urgent need for a second generation of HIV protease inhibitors. The continued exploration of our hydroxylaminepentanamide (HAPA) transition-state isostere series of HIV protease inhibitors, which initially resulted in the identification of Crixivan (indinavir sulfate, MK-639, L-735,524), has now yielded MK-944a (L-756,423). This compound is potent, is selective, and competitively inhibits HIV-1 PR with a K(i) value of 0.049 nM. It stops the spread of the HIV(IIIb)-infected MT4 lymphoid cells at 25.0-50.0 nM, even in the presence of alpha(1) acid glycoprotein, human serum albumin, normal human serum, or fetal bovine serum. MK-944a has a longer half-life in several animal models (rats, dogs, and monkeys) than indinavir sulfate and is currently in advanced human clinical trials.
authors.affiliation: Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Molecular Systems, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. bruce_dorsey@merck.com
authors.forename: B D
authors.initials: BD
authors.lastname: Dorsey
authors.forename: C
authors.initials: C
authors.lastname: McDonough
authors.forename: S L
authors.initials: SL
authors.lastname: McDaniel
authors.forename: R B
authors.initials: RB
authors.lastname: Levin
authors.forename: C L
authors.initials: CL
authors.lastname: Newton
authors.forename: J M
authors.initials: JM
authors.lastname: Hoffman
authors.forename: P L
authors.initials: PL
authors.lastname: Darke
authors.forename: J A
authors.initials: JA
authors.lastname: Zugay-Murphy
authors.forename: E A
authors.initials: EA
authors.lastname: Emini
authors.forename: W A
authors.initials: WA
authors.lastname: Schleif
authors.forename: D B
authors.initials: DB
authors.lastname: Olsen
authors.forename: M W
authors.initials: MW
authors.lastname: Stahlhut
authors.forename: C A
authors.initials: CA
authors.lastname: Rutkowski
authors.forename: L C
authors.initials: LC
authors.lastname: Kuo
authors.forename: J H
authors.initials: JH
authors.lastname: Lin
authors.forename: I W
authors.initials: IW
authors.lastname: Chen
authors.forename: S R
authors.initials: SR
authors.lastname: Michelson
authors.forename: M K
authors.initials: MK
authors.lastname: Holloway
authors.forename: J R
authors.initials: JR
authors.lastname: Huff
authors.forename: J P
authors.initials: JP
authors.lastname: Vacca
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002417:Cattle; D018929:Cell Culture Techniques; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004352:Drug Resistance, Microbial; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D000882:Haplorhini; D006801:Humans; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014545:Urinary Calculi / Q000139:chemically induced / Q000652:urine
chemical_list: D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D007189:Indans; D010879:Piperazines; C122089:L 756423