Balani S K, Pitzenberger S M, Schwartz M S, Ramjit H G, Thompson W J
Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA.
Drug Metab Dispos. 1995 Feb;23(2):185-9.
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.
L-689,502，N-[2(R)-羟基-1(S)-茚满基]-5(S)-(1,1-二甲基乙氧基羰基氨基)-4(S)-羟基-6-苯基-2(R)-(4-[2(R)-(4-吗啉基)乙氧基]苯基)甲基己酰胺，在体外是一种高效且特异性的人类免疫缺陷病毒1型（HIV-1）蛋白酶抑制剂。该化合物在大鼠肝切片中的代谢产生了四种主要代谢物和几种次要代谢物。主要代谢物被鉴定为吗啉-2-酮、3'(S)-羟基茚满和4'-羟基茚满类似物，以及母体化合物的4-O-葡萄糖醛酸共轭物。通过核磁共振光谱中的异核多量子相干和核Overhauser效应技术、质谱，和/或与标准品比较对代谢物进行了表征。两种次要代谢物同样被表征为2(R)-[4-(2-羧基甲氧基)苯基]甲基类似物和一种吗啉环降解产物。羟基茚满代谢物的活性低于L-689,502，而吗啉-2-酮和羧基甲氧基苯基类似物作为HIV-1蛋白酶抑制剂的效力分别约高6倍和11倍。
