title: Metabolites of L-735,524, a potent HIV-1 protease inhibitor, in human urine.
abstract: 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.
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: B H
authors.initials: BH
authors.lastname: Arison
authors.forename: L
authors.initials: L
authors.lastname: Mathai
authors.forename: L R
authors.initials: LR
authors.lastname: Kauffman
authors.forename: R R
authors.initials: RR
authors.lastname: Miller
authors.forename: R A
authors.initials: RA
authors.lastname: Stearns
authors.forename: I W
authors.initials: IW
authors.lastname: Chen
authors.forename: J H
authors.initials: JH
authors.lastname: Lin
mesh_terms: D002851:Chromatography, High Pressure Liquid; D017320:HIV Protease Inhibitors / Q000652:urine*; D015497:HIV-1 / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D019469:Indinavir; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D011725:Pyridines / Q000652:urine*; D013056:Spectrophotometry, Ultraviolet
chemical_list: D017320:HIV Protease Inhibitors; D011725:Pyridines; D019469:Indinavir