title: In vitro and in vivo metabolism and pharmacokinetics of BMS-562086, a potent and orally bioavailable corticotropin-releasing factor-1 receptor antagonist.
abstract: The absorption, distribution, metabolism, and excretion (ADME) and the pharmacokinetic characteristics of BMS-562086 [pexacerfont; 8-(6-methoxy-2-methyl-3-pyridinyl)-2,7-dimethyl-N-[(1R)-1-methylpropyl]pyrazolo(1,5-a)-1,3,5-triazin-4-amine (DPC-A69448)] were investigated in vitro and in animals to support its clinical development. BMS-562086 was orally bioavailable in rats, dogs, and chimpanzees, with an absolute oral bioavailability of 40.1, 58.8, and 58.5%, respectively. BMS-562086 was extensively metabolized in hepatocytes from all species and completely metabolized in rats. The primary biotransformation pathways found for BMS-562086 in both liver microsomal and hepatocyte preparations and in rats were similar. These included O-demethylation, hydroxylation at the N-alkyl side chain and N-dealkylation. Multiple cytochromes P450 including CYP3A4/5 were involved in the metabolic clearance of BMS-562086. Both renal and biliary excretion played a significant role in elimination of the metabolites of BMS-562086. The involvement of other metabolic enzymes in addition to CYP3A4/5 in elimination of BMS-562086 suggests a reduced potential for drug-drug interaction through modulation of CYP3A4/5. Chimpanzees proved to be a good animal model in predicting BMS-562086 human clearance. Virtual clinical trials performed with a population-based ADME simulator suggested that a minimal dose of 100 mg daily would provide sufficient drug exposure to achieve plasma concentrations above the projected human efficacious plasma concentration of BMS-562086 (> 500 nM). In summary, BMS-562086 exhibited favorable ADME and pharmacokinetic properties for further development.
authors.affiliation: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., P.O. Box 4000, Princeton, NJ 08543, USA. Lian.zhou@bms.com
authors.forename: Lian
authors.initials: L
authors.lastname: Zhou
authors.forename: Randy C
authors.initials: RC
authors.lastname: Dockens
authors.forename: Peggy
authors.initials: P
authors.lastname: Liu-Kreyche
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Grossman
authors.forename: Ramaswamy A
authors.initials: RA
authors.lastname: Iyer
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D018592:Cross-Over Studies; D004285:Dogs; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D002679:Pan troglodytes; D011485:Protein Binding / Q000502:physiology; D011720:Pyrazoles / Q000008:administration & dosage* / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013045:Species Specificity; D014227:Triazines / Q000008:administration & dosage* / Q000378:metabolism* / Q000493:pharmacokinetics; D000099052:CRF Receptor, Type 1
chemical_list: D011720:Pyrazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D014227:Triazines; D000099052:CRF Receptor, Type 1; C542342:pexacerfont