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

Rhesus monkeys were dosed orally with 10 mg/kg 5-chloro-3-phen-ylthioi ndole-2-carboxamide (L-734,005), a nonnucleoside human immunodeficienc y virus type 1 (HIV-1) reverse transcriptase inhibitor, in polyethylen e glycol 300. Plasma samples from these monkeys demonstrated greater b ioactivity in an HIV-1 reverse transcriptase inhibition assay than ant icipated from the parent compound concentrations as determined by an H PLC-UV assay. One major and three minor metabolites, as well as the pa rent compound, were detected in the plasma. One of the minor metabolit es was determined to be several-fold more active, and the major metabo lite 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 identi fied as a sulfone analog (L-737,126) of the parent compound by NMR and MS analyses. The less active major metabolite and two relatively inac tive minor metabolites were similarly identified as the sulfoxide, 4-h ydroxythiophenyl and 6-hydroxyindole analogs Of L-734,005. The synthet ic sulfone analog was highly potent against HIV-1, with a 95% inhibito ry concentration of 3.0 nM for the spread of virus infection in a cell culture.