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

Optimization of a series of N-1-cycloalkyl-4-aryl-5-(pyrimidin-4-yl)imidazo le 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. T e selectivity of these new inhibitors for p38 kinase versus eight other protein kinases is high and in all cases exceeds that of SB 203580. (C) 2001 Elsevier Science Ltd. All rights reserved.