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

J L Adams; J C Boehm; T F Gallagher; S Kassis; E F Webb; R Hall; M Sorenson; R Garigipati; D E Griswold; J C Lee

doi:10.1016/s0960-894x(01)00570-4

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

Bioorg Med Chem Lett. 2001 Nov 5;11(21):2867-70. doi: 10.1016/s0960-894x(01)00570-4.

Authors

J L Adams¹, J C Boehm, T F Gallagher, S Kassis, E F Webb, R Hall, M Sorenson, R Garigipati, D E Griswold, J C Lee

Affiliation

¹ Department of Medicinal Chemistry, GlaxoSmithKline Pharmaceuticals, PO Box 1539, King of Prussia, PA 19406, USA. [email protected]

PMID: 11597418
DOI: 10.1016/s0960-894x(01)00570-4

Abstract

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.

MeSH terms

Administration, Oral
Animals
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Imidazoles / chemistry
Imidazoles / pharmacology*
Lipoxygenase / drug effects
Liver / enzymology
Mice
Mitogen-Activated Protein Kinases / antagonists & inhibitors*
Prostaglandin-Endoperoxide Synthases / drug effects
Pyrimidines / chemistry*
Rats
p38 Mitogen-Activated Protein Kinases

Substances

Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Imidazoles
Pyrimidines
Lipoxygenase
Prostaglandin-Endoperoxide Synthases
Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases