Corticotropin-releasing factor subtype 1 (CRF1) receptor mediates stress-induced activation of the hypothalamic-pituitary-adrenal axis. Pexacerfont is a selective antagonist of CRF1 receptor with IC50 of 6.1 ± 0.6 nM for human CRF1 receptor. Pexacerfont was orally bioavailable in rats, dogs, and chimpanzees, with an absolute oral bioavailability of 40.1, 58.8, and 58.5%, respectively. Pexacerfont had an estimated hepaticextraction ratio of 0.32, 0.38, and 0.08 in rats, dogs, and chimpanzees, respectively. The average Vz of pexacerfont in the rats, dogs, andchimpanzee was 14.9, 28.2, and 4.2 l/kg, respectively. The terminal plasma elimination t1/2 values ranged from 13 to 43 h in rats, dogs, and chimpanzees. After oral administration, peak plasma concentrations (Tmax) of pexacerfont were achieved in less than 2 h for all three species, indicating a rapid oral absorption. 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 pexacerfont (> 500 nM)[1].
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