Journal : J. Med. Chem.
Title : Identification of MK-944a: a second clinical candidate from the hydroxylaminepentanamide isostere series of HIV protease inhibitors.
Year : 2000
Volume : 43
Issue : 18
First Page : 3386
Last Page : 3399
Authors : Dorsey BD, McDonough C, McDaniel SL, Levin RB, Newton CL, Hoffman JM, Darke PL, Zugay-Murphy JA, Emini EA, Schleif WA, Olsen DB, Stahlhut MW, Rutkowski CA, Kuo LC, Lin JH, Chen IW, Michelson SR, Holloway MK, Huff JR, Vacca JP.
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.
