Design, Synthesis, and Biological Evaluation of Novel Tri- and Tetrasubstituted Imidazoles as Highly Potent and Specific ATP-Mimetic Inhibitors of p38 MAP Kinase: Focus on Optimized Interactions with the Enzyme's Surface-Exposed Front Region.

[摘要]：The synthesis, biol. testing, and SAR of novel 2,4,5- and 1,2,4,5-substituted 2-thioimidazoles, e.g., I are described. Amino, oxy, or thioxy substituents at the 2-position of the pyridinyl moiety were evaluated for their contributions to inhibitor potency and selectivity against p38 mitogen activated protein kinase (p38 MAPK) as well as for the ability to minimize cytochrome P 450 (CYP450) inhibition. Incorporation of polar substituted (cyclo)aliph. amino substituents (e.g., tetrahydropyranylamino), which pos. interacted with the surface-exposed front region (hydrophobic region II) of the enzyme led to the identification of extremely potent p38 MAPK inhibitors with p38 IC50 values in the low nanomolar range. Approx. 90 pyridinylimidazole-based compds. with a range of potencies against p38a MAP kinase were further investigated for their ability to inhibit the from human whole blood. Some of the most promising drug candidates underwent selectivity profiling against a panel of 17 different kinases besides p38a and/or were tested for their interaction potential toward a no. of metabolically relevant CYP450 isoenzymes.

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