PT  - JOURNAL ARTICLE
AU  - S K Balani
AU  - S M Pitzenberger
AU  - M S Schwartz
AU  - H G Ramjit
AU  - W J Thompson
TI  - Metabolism of L-689,502 by rat liver slices to potent HIV-1 protease inhibitors.
DP  - 1995 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 185--189
VI  - 23
IP  - 2
4099  - http://dmd.aspetjournals.org/content/23/2/185.short
4100  - http://dmd.aspetjournals.org/content/23/2/185.full
SO  - Drug Metab Dispos1995 Feb 01; 23
AB  - L-689,502, N-[2(R)-hydroxy-1(S)-indanyl]-5(S)-(1,1-dimethylethoxy- carbonyl-amino)-4(S)-hydroxy-6-phenyl-2(R)-(4-[2(R)-(4-morpholinyl) ethoxy]phenyl)methylhexamide, is a potent and specific inhibitor of human immunodeficiency virus-type 1 (HIV-1) protease in vitro. Metabolism of this compound in rat liver slices produced four major and several minor metabolites. The major metabolites were identified as morpholin-2-one, 3'(S)-hydroxyindan and 4'-hydroxyindan analogs, and a 4-O-glucuronic acid conjugate of the parent compound. The metabolites were characterized by Heteronuclear Multiple Quantum Coherence and Nuclear Overhauser Effect techniques in NMR spectroscopy, by MS, and/or comparison with authentic standards. Two of the minor metabolites were similarly characterized as a 2(R)-[4-(2-carboxymethoxy)phenyl]methyl analog and a product with a degraded morpholino ring. The hydroxyindan metabolites were lower in activity than L-689,502, whereas the morpholin-2-one and carboxymethoxyphenyl analogs were approximately 6- and 11-fold more potent as inhibitors of HIV-1 protease, respectively.