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

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.

[1]  G. Bemis,et al.  The structural basis for the specificity of pyridinylimidazole inhibitors of p38 MAP kinase. , 1997, Chemistry & biology.

[2]  C W Qualls,et al.  Comparative Biochemical and Morphometric Changes Associated with Induction of the Hepatic Mixed Function Oxidase System in the Rat , 1991, Toxicologic pathology.

[3]  J. Adams,et al.  Differentiation in vivo of classical non-steroidal antiinflammatory drugs from cytokine suppressive antiinflammatory drugs and other pharmacological classes using mouse tumour necrosis factor alpha production. , 1993, Drugs under experimental and clinical research.

[4]  J. Wildeman,et al.  Chemistry of sulfonylmethyl isocyanides. 12. Base-induced cycloaddition of sulfonylmethyl isocyanides to carbon,nitrogen double bonds. Synthesis of 1,5-disubstituted and 1,4,5-trisubstituted imidazoles from aldimines and imidoyl chlorides , 1977 .

[5]  Philip R. Cohen,et al.  SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin‐1 , 1995, FEBS letters.

[6]  P. Ortiz de Montellano,et al.  Active-site topologies of human CYP2D6 and its aspartate-301 --> glutamate, asparagine, and glycine mutants. , 1996, Archives of biochemistry and biophysics.

[7]  J. Boehm,et al.  1-substituted 4-aryl-5-pyridinylimidazoles: a new class of cytokine suppressive drugs with low 5-lipoxygenase and cyclooxygenase inhibitory potency. , 1996, Journal of medicinal chemistry.

[8]  B. Testa,et al.  Inhibitors of Cytochrome P-450s and their mechanism of action. , 1981, Drug metabolism reviews.

[9]  R. Novak,et al.  The induction of cytochrome P4502E1 by nitrogen- and sulfur-containing heterocycles: expression and molecular regulation. , 1993, Toxicology and applied pharmacology.

[10]  J. Boehm,et al.  Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase. , 1997, Bioorganic & medicinal chemistry.

[11]  P. Bender,et al.  Bicyclic Imidazoles as a Novel Class of Cytokine Biosynthesis Inhibitors , 1993, Annals of the New York Academy of Sciences.

[12]  Jerry L. Adams,et al.  A protein kinase involved in the regulation of inflammatory cytokine biosynthesis , 1994, Nature.

[13]  F. Effenberger,et al.  Synthesen in der heterocyclischen Reihe, IV. Synthesen heterocyclischer Aldehyde. Pyrimidinaldehyd‐(4) , 1964 .