Pyrimidinylimidazole inhibitors of CSBP/P38 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes

Pyrimidine analogs of the pyridinylimidazole 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...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 1998-11, Vol.8 (22), p.3111-3116
Main Authors: Adams, Jerry L., Boehm, Jeffrey C., Kassis, Shouki, Gorycki, Peter D., Webb, Edward F., Hall, Ralph, Sorenson, Margaret, Lee, John C., Ayrton, Andrew, Griswold, Don E., Gallagher, Timothy F.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors - chemical synthesis
Humans
Imidazoles - chemical synthesis
Imidazoles - pharmacology
Medical sciences
Mice
Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
Pharmacology. Drug treatments
Pyrimidines - chemical synthesis
Pyrimidines - pharmacology
Rats
Structure-Activity Relationship
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Summary:Pyrimidine analogs of the pyridinylimidazole 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. The substitution of pyrimidin-4-yl, 2-methoxypyrimidin-4-yl, or 2-methylaminopyrimidin-4-yl for pyridin-4-yl dissociates CSBP/p38 kinase from P450 inhibition and furthermore improves oral activity.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(98)00549-6