title: Application of a deuterium replacement strategy to modulate the pharmacokinetics of 7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole, a novel CRF1 antagonist.
abstract: Deuterium isotope effects were evaluated as a strategy to optimize the pharmacokinetics of 7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole (NVS-CRF38), a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist. In an attempt to suppress O-demethylation of NVS-CRF38 without losing activity against the CRF1 receptor, the protons at the site of metabolism were replaced with deuterium. For in vitro and in vivo studies, intrinsic primary isotope effects (KH/KD) were determined by the ratio of intrinsic clearance (CLint) obtained for NVS-CRF38 and deuterated NVS-CRF38. In vitro kinetic isotope effects (KH/KD) were more pronounced when CLint values were calculated based on the rate of formation of the O-desmethyl metabolite (KH/KD ∼7) compared with the substrate depletion method (KH/KD ∼2). In vivo isotope effects were measured in rats after intravenous (1 mg/kg) and oral (10 mg/kg) administration. For both administration routes, isotope effects calculated from in vivo CLint corresponding to all biotransformation pathways were lower (KH/KD ∼2) compared with CLint values calculated from the O-demethylation reaction alone (KH/KD ∼7). Comparative metabolite identification studies were undertaken using rat and human microsomes to explore the potential for metabolic switching. As expected, a marked reduction of the O-demethylated metabolite was observed for NVS-CRF38; however, levels of NVS-CRF38's other metabolites increased, compensating to some extent for the isotope effect.
authors.affiliation: Novartis Institutes for Biomedical Research, Horsham, West Sussex, UK (R.A.S., G.W., B.S., J.M.); and Novartis Pharma AG, Novartis Institutes for Biomedical Research, Drug Metabolism and Pharmacokinetics, Basel, Switzerland (F.P., O.K., J.A.K.).
authors.forename: Rowan A
authors.initials: RA
authors.lastname: Stringer
authors.forename: Gareth
authors.initials: G
authors.lastname: Williams
authors.forename: Franck
authors.initials: F
authors.lastname: Picard
authors.forename: Bindi
authors.initials: B
authors.lastname: Sohal
authors.forename: Olivier
authors.initials: O
authors.lastname: Kretz
authors.forename: Jeff
authors.initials: J
authors.lastname: McKenna
authors.forename: Joel A
authors.initials: JA
authors.lastname: Krauser
mesh_terms: D000284:Administration, Oral; D000818:Animals; D003903:Deuterium / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D010080:Oxazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011522:Protons; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D000099052:CRF Receptor, Type 1
chemical_list: C000593013:7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo(5,1-b)oxazole; D010080:Oxazoles; D011522:Protons; D011720:Pyrazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003903:Deuterium