CP671305

CP671305 is a potent, orally active, selective inhibitor of phosphodiesterase-4-D, and possesses high activities. In Vitro: CP-671,305 is identified as a substrate of MRP2 and BCRP, but not MDR1. CP-671,305 is a substrate of human OATP2B1 with a high affinity (K_m=4 μM) but not a substrate for human OATP1B1 or OATP1B3. CP-671,305 displays high affinity (K_m=12 μM) for rat hepatic Oatp1a4^[1]. CP-671,305 does not exhibit competitive inhibition of the five major cytochrome P450 enzymes, namely CYP1A2, 2C9, 2C19, 2D6 and 3A4 (IC₅₀s > 50 μM). Likewise, no time-dependent inactivation of the five major cytochrome P450 enzymes is discernible with CP-671,305^[2]. In Vivo: CP-671,305 pharmacokinetics are largely unaltered, and compromised biliary clearance of CP-671,305 is compensated by increased urinary clearance^[1]. CP-671,305 demonstrates generally favourable pharmacokinetic properties, systemic plasma clearance after intravenous administration is low in Sprague-Dawley rats (9.60 ± 1.16 mL/min/kg), beagle dogs (2.90 ± 0.81 mL/min/kg) and cynomolgus monkeys (2.94 ± 0.87 mL/min/kg) resulting in plasma half-lives > 5 h. Moderate to high bioavailability in rats (43-80%), dogs (45%) and monkeys (26%) is observed after oral dosing. In rats, oral pharmacokinetics are dose dependent over the dose range studied (10 and 25 mg/kg)^[2].