Balani S K, Arison B H, Mathai L, Kauffman L R, Miller R R, Stearns R A, Chen I W, Lin J H
Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA.
Drug Metab Dispos. 1995 Feb;23(2):266-70.
L-735,524, N-[2(R)-hydroxy-1(S)-indanyl]-5-(2(S)-(1,1- dimethylethylaminocarbonyl)-4-[(pyridin-3-yl)methyl]piperazin++ +-1-yl)-4(S)- hydroxy-2(R)-phenylmethylpentanamide, is a potent and specific inhibitor of the human immunodeficiency virus type 1 protease and is undergoing clinical evaluation. In an initial clinical study, noninfected male volunteers were administered single, 1000 mg oral doses of nonlabeled compound. Urine samples were collected over a period of 48 hr. Metabolic profile of the urine was determined by HPLC-UV comparison with that from a human liver slice incubation of radiolabeled L-735,524. Seven significant metabolites were isolated from pooled human urine, and were characterized by NMR, MS, and/or chromatographic comparisons with authentic standards. The major metabolic pathways were identified as: a) glucuronidation at the pyridine nitrogen to yield a quaternized ammonium conjugate, b) pyridine N-oxidation, c) para-hydroxylation of the phenylmethyl group, d) 3'-hydroxylation of the indan, and e) N-depyridomethylation. A minor product was identified as 2',3'-trans-dihydroxyindan analog. Urinary excretion of L-735,524 and its metabolites represented a minor pathway of elimination. The intact parent compound seemed to be the major component in the urine, whereas the level of each metabolite was relatively low.
L-735,524，即N-[2(R)-羟基-1(S)-茚满基]-5-(2(S)-(1,1-二甲基乙氨基羰基)-4-[(吡啶-3-基)甲基]哌嗪-1-基)-4(S)-羟基-2(R)-苯甲基戊酰胺，是一种高效且特异的人类免疫缺陷病毒1型蛋白酶抑制剂，正在进行临床评估。在一项初始临床研究中，给未感染的男性志愿者单次口服1000毫克未标记化合物。在48小时内收集尿液样本。通过与放射性标记的L-735,524在人肝切片孵育后的尿液进行HPLC-UV比较，确定尿液的代谢谱。从合并的人尿中分离出七种主要代谢物，并通过核磁共振、质谱和/或与标准品的色谱比较进行表征。主要代谢途径确定为：a)吡啶氮位的葡萄糖醛酸化，生成季铵共轭物；b)吡啶N-氧化；c)苯甲基的对羟基化；d)茚满的3'-羟基化；e)N-去吡啶甲基化。一种次要产物被鉴定为2',3'-反式二羟基茚满类似物。L-735,524及其代谢物经尿液排泄是次要的消除途径。完整的母体化合物似乎是尿液中的主要成分，而每种代谢物的水平相对较低。
