Novel substituted pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes
Novel substituted pyridinyl imidazoles as potent anticytokine agents with low activity against hepatic cytochrome P450 enzymes
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DOI：
10.1021/jm030766k
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发表时间：
2003-07-17
影响因子：
7.3
通讯作者：
Albrecht, W
中科院分区：
文献类型：
--
作者：
Laufer, SA;Wagner, GK;Albrecht, W
合成了一系列p38 MAP（mitogen-activated protein）激酶的多取代吡啶-4-基咪唑抑制剂，作为小分子抗细胞因子药物和治疗慢性炎症性疾病的候选药物。在吡啶基和咪唑部分的取代基的选择性抑制p38没有伴随细胞色素P450相互作用的贡献进行了评价。将1-苯乙基（7 e，p38：IC 50 0.38 μ M）或乙酰基取代基置于几种2-氨基吡啶咪唑的环外氮上，导致鉴定出有效的p38抑制剂，其在效力上超过起始先导物ML 3375（p38：IC 50 0.63 μ M）。一个初步的建模研究相关的增强生物活性的7 e的1-苯乙氨基侧链和疏水口袋接近p38的连接区之间的一种新的相互作用。该系列中最活跃的p38抑制剂在功能性PBMC（外周血单核细胞）和全血测定中保持其功效。此外，细胞色素P450的相互作用，这已被链接到模型p38抑制剂观察到的肝毒性，是非常有效地减少通过引入四甲基哌啶取代基的1位的咪唑核。两种结构特征的组合提供了14 c（p38：0.34 μ M，在10 μ M时抑制CYP 1A 2 0%，2C 9 2.6%，2C 19 7.6%），选择其用于进一步开发。
A series of polysubstituted pyridin-4-yl imidazole inhibitors of p38 MAP (mitogen-activated protein) kinase was prepared as small molecular anticytokine agents and drug candidates for the treatment of chronic inflammatory diseases. The contribution of substituents at the pyridinyl and imidazole moiety to selective inhibition of p38 without concomitant cytochrome P450 interaction was evaluated. Placement of a 1-phenylethyl (7e, p38: IC50 0.38 muM) or acetyl substituent at the exocyclic nitrogen of several 2-aminopyridine imidazoles led to the identification of potent p38 inhibitors which exceeded the starting lead ML 3375 (p38: IC50 0.63 muM) in potency. A preliminary modeling study related the enhanced bioactivity of 7e to a novel interaction between its 1-phenylethylamino side chain and a hydrophobic pocket close to the linker region of p38. The most active p38 inhibitors in this series maintained their efficacy in functional PBMC (peripheral blood mononuclear cells) and whole blood assays. Moreover, cytochrome P450 interaction, which has been linked to the liver toxicity observed for model p38 inhibitors, was very efficiently reduced through introduction of a tetramethylpiperidine substituent at the 1 position of the imidazole nucleus. Combination of both structural features provided 14c (p38: 0.34 muM, inhibition of CYP1A2 0%,2C9 2.6%,2C19 7.6% at 10muM), which was selected for further development.