title: Evidence for a 1,2-hydride shift in the microsomal metabolism of the heterocycle L-158,338, a nonpeptide angiotensin II receptor antagonist.
abstract: L-158,338 is an imidazo[4,5-b]pyridine derivative that is a potent and highly selective angiotensin II receptor antagonist. Rat liver microsomal metabolism of [C6-3H]L-158,338 gave a major metabolite that was monohydroxylated at the C6 position of the imidazo-pyridine but showed partial retention of the radiolabel. This biotransformation necessitated a shift of the radiolabel from the C6 position to another site within the molecule. We have investigated the mechanism of this biotransformation using 3H-, 3H/14C-, and 2H-labeled L-158,338. Metabolites were identified by FAB/MS, LC/MS, and 1H-NMR. Results of these studies show that the microsomal metabolism of L-158,338 to its C6-monohydroxylated derivative was mediated by a 1,2 hydride shift.
authors.affiliation: Department of Animal and Exploratory Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065-0900.
authors.forename: R A
authors.initials: RA
authors.lastname: Stearns
authors.forename: R R
authors.initials: RR
authors.lastname: Miller
authors.forename: B H
authors.initials: BH
authors.lastname: Arison
authors.forename: A
authors.initials: A
authors.lastname: Rosegay
authors.forename: J L
authors.initials: JL
authors.lastname: Smith
authors.forename: N B
authors.initials: NB
authors.lastname: Mantlo
authors.forename: S H
authors.initials: SH
authors.lastname: Chiu
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D006900:Hydroxylation; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D011725:Pyridines; C083194:L 158338