title: Pyrimidinylimidazole inhibitors of CSBP/p38 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes.
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.
authors.affiliation: SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Adams
authors.forename: J C
authors.initials: JC
authors.lastname: Boehm
authors.forename: S
authors.initials: S
authors.lastname: Kassis
authors.forename: P D
authors.initials: PD
authors.lastname: Gorycki
authors.forename: E F
authors.initials: EF
authors.lastname: Webb
authors.forename: R
authors.initials: R
authors.lastname: Hall
authors.forename: M
authors.initials: M
authors.lastname: Sorenson
authors.forename: J C
authors.initials: JC
authors.lastname: Lee
authors.forename: A
authors.initials: A
authors.lastname: Ayrton
authors.forename: D E
authors.initials: DE
authors.lastname: Griswold
authors.forename: T F
authors.initials: TF
authors.lastname: Gallagher
mesh_terms: D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011743:Pyrimidines; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases