TY - JOUR T1 - Identification and characterization of a selective human carbonyl reductase 1 substrate JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.118.082487 SP - dmd.118.082487 AU - Diane Ramsden AU - Dustin Smith AU - Raquel Arenas AU - Kosea Frederick AU - Matthew A Cerny Y1 - 2018/01/01 UR - http://dmd.aspetjournals.org/content/early/2018/08/01/dmd.118.082487.abstract N2 - During drug discovery efforts targeting inhibition of cytochrome P450 11B2 (CYP11B2)-mediated production of aldosterone as a therapeutic approach for the treatment of chronic kidney disease and hypertension, (S)-6-(5-fluoro-4-(1-hydroxyethyl)pyridin-3-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (1) was identified as a potent and selective inhibitor of CYP11B2. Pre-clinical studies characterized 1 as low clearance in both in vitro test systems and in vivo in pre-clinical species. Despite low metabolic conversion, an active ketone metabolite (2), was identified from in vitro metabolite identification studies. Due to the inhibitory activity of 2 against CYP11B2 as well as the potential for it to undergo reductive metabolism back to 1, the formation and elimination of 2 were characterized and are the focus of this manuscript. A series of in vitro investigations determined that 1 was slowly oxidized to 2 by P450 2D6, 3A4, and 3A5, followed by stereoselective reduction back to 1 and not its enantiomer (3). Importantly, reduction of 2 was mediated by an NADPH-dependent, cytosolic enzyme. Studies with human cytosolic fractions from multiple tissues, selective inhibitors, and recombinantly expressed enzymes indicated that carbonyl reductase 1 (CBR1) is responsible for this transformation in humans. Carbonyl reduction is emerging as an important pathway for endogenous and xenobiotic metabolism. With a lack of selective substrates and inhibitors to enable characterization of the involvement of CBR1, 2 could be a useful probe to assess CBR1 activity in vitro in both subcellular fractions and in cell-based systems. ER -