RT Journal Article
SR Electronic
T1 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.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 598
OP 604
VO 21
IS 4
A1 Balani, S K
A1 Goldman, M E
A1 Kauffman, L R
A1 Varga, S L
A1 O'Brien, J A
A1 Smith, S J
A1 Olah, T V
A1 Ramjit, H G
A1 Schorn, T W
A1 Pitzenberger, S M
YR 1993
UL http://dmd.aspetjournals.org/content/21/4/598.abstract
AB 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.