title: Metabolism of L-689,502 by rat liver slices to potent HIV-1 protease inhibitors.
abstract: 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.
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Balani
authors.forename: S M
authors.initials: SM
authors.lastname: Pitzenberger
authors.forename: M S
authors.initials: MS
authors.lastname: Schwartz
authors.forename: H G
authors.initials: HG
authors.lastname: Ramjit
authors.forename: W J
authors.initials: WJ
authors.lastname: Thompson
mesh_terms: D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005965:Glucuronates / Q000378:metabolism / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D007189:Indans / Q000378:metabolism / Q000494:pharmacology; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism*; D008297:Male; D009025:Morpholines / Q000378:metabolism* / Q000493:pharmacokinetics; D010455:Peptides / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D005965:Glucuronates; D017320:HIV Protease Inhibitors; D007189:Indans; D009025:Morpholines; D010455:Peptides; C072111:L 689502