Identification and Characterization of a Selective Human Carbonyl Reductase 1 Substrate
| Autor: | Matthew A. Cerny, Raquel Arenas, Kosea Frederick, Dustin Smith, Diane Ramsden |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
CBR1 Carbonyl Reductase Pyridines Metabolite Pharmaceutical Science 030226 pharmacology & pharmacy Substrate Specificity 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine In vivo Drug Discovery Animals Cytochrome P-450 CYP11B2 Humans Carbonyl Reductase (NADPH) Renal Insufficiency Chronic Pharmacology chemistry.chemical_classification biology Carbonyl reduction Cytochrome P450 030104 developmental biology Enzyme Biochemistry chemistry Hypertension biology.protein Drug metabolism |
| Zdroj: | Drug metabolism and disposition: the biological fate of chemicals. 46(10) |
| ISSN: | 1521-009X |
| Popis: | 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. Preclinical studies characterized 1 as low clearance in both in vitro test systems and in vivo in preclinical 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 cytochrome P450s 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. |
| Databáze: | OpenAIRE |
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