Identification of MK-944a: a second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors

  • J Med Chem. 2000 Sep 7;43(18):3386-99. doi: 10.1021/jm9903848.
B D Dorsey  1 ,  C McDonough ,  S L McDaniel ,  R B Levin ,  C L Newton ,  J M Hoffman ,  P L Darke ,  J A Zugay-Murphy ,  E A Emini ,  W A Schleif ,  D B Olsen ,  M W Stahlhut ,  C A Rutkowski ,  L C Kuo ,  J H Lin ,  I W Chen ,  S R Michelson ,  M K Holloway ,  J R Huff ,  J P Vacca
Affiliations
  • 1. Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Molecular Systems, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. [email protected]
PMID: 10978186 DOI: 10.1021/jm9903848
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.

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