Pyrimidinylimidazole inhibitors of p38: cyclic N-1 imidazole substituents enhance p38 kinase inhibition and oral activity

• Published in: Bioorganic & medicinal chemistry letters 2001-11, Vol.11 (21), p.2867-2870
• Main Authors: Adams, Jerry L., Boehm, Jeffrey C., Gallagher, Timothy F., Kassis, Shouki, Webb, Edward F., Hall, Ralph, Sorenson, Margaret, Garigipati, Ravi, Griswold, Don E., Lee, John C.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cytochrome P-450 Enzyme Inhibitors; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Imidazoles - chemistry; Imidazoles - pharmacology; Lipoxygenase - drug effects; Liver - enzymology; Medical sciences; Mice; Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases; Pharmacology. Drug treatments; Prostaglandin-Endoperoxide Synthases - drug effects; Pyrimidines - chemistry; Rats
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(01)00570-4

Optimization of a series of N-1-cycloalkyl-4-aryl-5-(pyrimidin-4-yl)imidazole inhibitors of p38 kinase is reported. Oral administration of inhibitors possessing a cyclohexan-4-ol or piperidin-4-yl group at N-1 in combination with alkoxy, amino(alkyl), phenoxy and anilino substitution at the 2-position of the pyrimidine was found to potently inhibit LPS-induced TNF in mice and rats. The selectivity of these new inhibitors for p38 kinase versus eight other protein kinases is high and in all cases exceeds that of SB 203580. A series of N-1-cycloalkyl-4-aryl-5-(pyrimidin-4-yl)imidazole p38 kinase inhibitors has been optimized for in vitro and in vivo potency. Based upon its overall profile, SB 242235 was chosen as a clinical development candidate for evaluation in the treatment of rheumatoid arthritis.