title: Biotransformation of 5-chloro-3-phenylthioindole-2-carboxamide (L-734,005) in rhesus monkeys and rat liver microsomes to a potent HIV-1 reverse transcriptase inhibitor.
abstract: Rhesus monkeys were dosed orally with 10 mg/kg 5-chloro-3-phenylthioindole-2-carboxamide (L-734,005), a nonnucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, in polyethylene glycol 300. Plasma samples from these monkeys demonstrated greater bioactivity in an HIV-1 reverse transcriptase inhibition assay than anticipated from the parent compound concentrations as determined by an HPLC-UV assay. One major and three minor metabolites, as well as the parent compound, were detected in the plasma. One of the minor metabolites was determined to be several-fold more active, and the major metabolite one-half as active as the parent compound in the inhibition assay. Identical metabolites were formed during an incubation of L-734,005 with rat liver microsomes. The most active minor metabolite was identified as a sulfone analog (L-737,126) of the parent compound by NMR and MS analyses. The less active major metabolite and two relatively inactive minor metabolites were similarly identified as the sulfoxide, 4-hydroxythiophenyl and 6-hydroxyindole analogs of L-734,005. The synthetic sulfone analog was highly potent against HIV-1, with a 95% inhibitory concentration of 3.0 nM for the spread of virus infection in a cell culture.
authors.affiliation: Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486.
authors.forename: S K
authors.initials: SK
authors.lastname: Balani
authors.forename: M E
authors.initials: ME
authors.lastname: Goldman
authors.forename: L R
authors.initials: LR
authors.lastname: Kauffman
authors.forename: S L
authors.initials: SL
authors.lastname: Varga
authors.forename: J A
authors.initials: JA
authors.lastname: O'Brien
authors.forename: S J
authors.initials: SJ
authors.lastname: Smith
authors.forename: T V
authors.initials: TV
authors.lastname: Olah
authors.forename: H G
authors.initials: HG
authors.lastname: Ramjit
authors.forename: T W
authors.initials: TW
authors.lastname: Schorn
authors.forename: S M
authors.initials: SM
authors.lastname: Pitzenberger
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005260:Female; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors; D013056:Spectrophotometry, Ultraviolet
chemical_list: D000998:Antiviral Agents; D007211:Indoles; D018894:Reverse Transcriptase Inhibitors; C083192:5-chloro-3-phenylthioindole-2-carboxamide; D054303:HIV Reverse Transcriptase