In Vitro and In Vivo Metabolism and Pharmacokinetics of BMS-562086, a Potent and Orally Bioavailable Corticotropin-Releasing Factor-1 Receptor Antagonist

Abstract

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 Ndealkylation. 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.

The CRF1 Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects

“…The in vivo HPA-axis suppressing activity of verucerfont in patients was predicted by rat data, which showed a potent and lasting suppression of ACTH output when a maximal activation of CRF drive was induced through adrenalectomy. Utility of the adrenalectomized rat assay for predicting in vivo CRF1 antagonist activity is further supported by the observations that another CRF1 antagonist, pexacerfont (Zhou et al, 2012), lacked activity in the rat assay, and was similarly unable to block the dex-CRF response in AD patients in a previous study (Kwako et al, 2015).…”

The Corticotropin Releasing Hormone-1 (CRH1) Receptor Antagonist Pexacerfont in Alcohol Dependence: A Randomized Controlled Experimental Medicine Study

“…Estimating central RO achieved by CRH1 antagonists is therefore critical for properly interpreting clinical results obtained with these drugs in behavioral disorders, but remains challenging in the absence of a displaceable PET ligand. Modeling has predicted central RO in excess of 80% following pexacerfont loading with 300 mg daily for a week followed by the administration of 100 mg daily (Coric et al, 2010;Zhou et al, 2012), but considerable uncertainty is inherent in these predictions. It has therefore remained unclear whether negative clinical findings with CRH1 antagonists like pexacerfont in generalized anxiety disorder (GAD; Coric et al, 2010) reflect a true failure of the mechanism, or insufficient CNS exposure.…”

“…They received loading with 300 mg of pexacerfont given once daily for the first 7 days, followed by 100 mg once daily for 23 days, or placebo. Dosing was based on pharmacokinetic data indicating that by the end of a 1-week-loading phase, 490% of patients are above the projected human efficacious plasma pexacerfont concentration of 500 nM (Coric et al, 2010;Zhou et al, 2012).…”

“…Here, we carried out a double-blind, placebo-controlled experimental medicine study to evaluate pexacerfont, a selective, orally available and brain-penetrant CRH1 antagonist with potent anti-anxiety activity in experimental animals in the absence of HPA axis effects (Gilligan et al, 2009;Zhou et al, 2012). We enrolled anxious, treatment-seeking alcoholdependent patients, and examined whether pexacerfont would reduce their stress-induced craving for alcohol or neural responses to stressful stimuli presented during functional magnetic resonance imaging (fMRI) sessions.…”

Behavioral, biological, and chemical perspectives on targeting CRF1 receptor antagonists to treat alcoholism

“…These include verucerfont (NBI-77860/GSK561679; (Tellew et al, 2010) and emicerfont (GW876008; (Di Fabio et al, 2008). In addition, pexacerfont (Gilligan et al, 2009a), the potent ( IC 50 = 6.1 nM) lead candidate from Bristol Myers Squibb, is a substituted pyrazolo[1,5- a ]-1,3,5-triazine that showed good pharmacokinetics in rat, dog, and nonhuman primate models, no evidence of gastrointestinal or respiratory toxicity, and mild renal effects at doses ~1 order greater than those needed to substantially occupy brain CRF receptors (Gilligan et al, 2009a; Zhou et al, 2012). Supporting its therapeutic potential, pexacerfont was more potent than MTIP in reversing acute alcohol withdrawal-induced anxiety-like behavior of rats in the elevated plus-maze.…”