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-methoxy-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 > 4h. 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.
Ward
K W
KW
Preclinical Drug Discovery, Cardiovascular, Urogenitary, and Oncology Centre for Excellence in Drug Discovery, GlaxoSmithKline R&D, King of Prussia, PA 19406, USA. keith_w_ward@gsk.com
Proksch
J W
JW
Salyers
K L
KL
Azzarano
L M
LM
Morgan
J A
JA
Roethke
T J
TJ
McSurdy-Freed
J E
JE
Levy
M A
MA
Smith
B R
BR
D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D004058:Diffusion; D004285:Dogs; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics*; D008252:Macaca fascicularis; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D011725:Pyridines / Q000493:pharmacokinetics*; D051381:Rats; D013045:Species Specificity; D048051:p38 Mitogen-Activated Protein Kinases
D001798:Blood Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; C403289:SB 242235; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases