Pyrimidinylimidazole inhibitors of CSBP/p38 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes

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

doi:10.1016/s0960-894x(98)00549-6

Pyrimidinylimidazole inhibitors of CSBP/p38 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes

Bioorg Med Chem Lett. 1998 Nov 17;8(22):3111-6. doi: 10.1016/s0960-894x(98)00549-6.

Authors

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

Affiliation

¹ SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.

PMID: 9873686
DOI: 10.1016/s0960-894x(98)00549-6

Abstract

Pyrimidine analogs of the pyrimidinylimidazole class of CSBP/p38 kinase inhibitors were prepared in an effort to reduce the potent inhibition of hepatic cytochrome P450 observed for the pyridinyl compounds. The substitution of pyrimidin-4-yl, 2-methoxypyrimidin-4-yl, or 2-methylaminopyrimidin-4-yl for pyridin-4-yl effectively dissociates CSBP/p38 kinase from P450 inhibition for this series and furthermore achieves an increase in oral activity.

MeSH terms

Animals
Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
Cytochrome P-450 Enzyme Inhibitors*
Enzyme Inhibitors / chemical synthesis*
Humans
Imidazoles / chemical synthesis*
Imidazoles / pharmacology
Mice
Mitogen-Activated Protein Kinases*
Pyrimidines / chemical synthesis*
Pyrimidines / pharmacology
Rats
Structure-Activity Relationship
p38 Mitogen-Activated Protein Kinases

Substances

Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Imidazoles
Pyrimidines
Calcium-Calmodulin-Dependent Protein Kinases
Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases