2. Academic Validation
  3. Identification of MK-944a: a second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors

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

Affiliation

  • 1 Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Molecular Systems, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. bruce_dorsey@merck.com
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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