Pexacerfont

Pexacerfont is a selective corticotropin-releasing factor (CRF₁) receptor antagonist with IC₅₀ of 6.1±0.6 nM for human CRF₁ receptor. IC50 & Target: IC50: 6.1±0.6 nM (human CRF₁ receptor)^[1] In Vitro: Pexacerfont demonstrates a potent and specific inhibitory effect (IC₅₀=6.1 ± 0.6 nM) toward human CRF₁ receptor and has greater than 1000-fold lower affinity (IC₅₀>1000 nM) for the CRF-binding protein and biogenic amine receptors^[1]. In Vivo: Pexacerfont (BMS-562086) is active in rats (1-10 mg/kg, orally) in the defensive withdrawal and elevated plus maze models of anxiety. After the intravenous bolus dose, the plasma Pexacerfont concentrations exhibited a multiexponential decline in rats, dogs, and chimpanzees. The CL_p of Pexacerfont was higher in rats (17.9 mL/kg per min) and dogs (11.6 mL/kg per min) than in chimpanzees (2.0 mL/kg per min). Assuming the value of CL_p of Pexacerfont approximates the value of CL_b in these three species, Pexacerfont has an estimated hepatic extraction ratio of 0.32, 0.38, and 0.08 in rats, dogs, and chimpanzees, respectively (calculated by dividing CL_p by respective hepatic blood flow, 55.2, 30.9, and 25.5 mL/kg per min for rats, dogs, and chimpanzees). The assumption that CL_b is equal to CL_p is reasonable at least in rats, where the blood to plasma concentration ratio of BMS-562086-equivalent radioactivity was 0.95 at 1 h postdose^[1].