Sb-242235, A Selective Inhibitor Of P38 Mitogen-Activated Protein Kinase. I: Preclinical Pharmacokinetics

1. SB-242235 (1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-metlioxy-4-pyrimidinyl) imidazole) is a potent and selective p38 MAP kinase inhibitor that may be an effective therapy for cytokine-mediated diseases such as autoimmune or inflammatory diseases. The present studies were conducted to evaluate the pharmacokinetics of SB-242235 in several preclinical species, including rat, dog and monkey.2. SB-242235 demonstrates generally favourable pharmacokinetic properties in all species examined, Systemic plasma clearance was high in rat, but in the non-rodent species SB-242235 demonstrated low, to moderate clearance with plasma half-lives > 4 h. Oral bioavailability in each preclinical species was high. In rat and monkey, SB-242235 demonstrated non-linear elimination kinetics that manifested as a decrease in clearance with increasing dose and apparent oral bioavailability > 100'%. at high oral doses. Furthermore, SB-242235 displayed concentration-dependent plasma protein binding over a concentration range of 1000-10,000 ng ml(1).3. In conclusion, SB-242235 demonstrates high oral bioavailability across the major preclinical species, and may thus be a useful tool compound for investigation of the role of p38 inhibition in various disease states. However, the observations of non-linear protein binding and disposition also suggest the need for caution in the design of and data interpretation from such studies.