Dysregulation of calpains 1 and 2 has been implicated in a variety of pathological disorders including ischemia/reperfusion injuries, kidney diseases, cataract formation, and neurodegenerative diseases such as Alzheimer’s disease (AD). 2-(3-Phenyl-1H)-pyrazol-1-yl)nicotinamides represent a series of novel and potent calpain inhibitors with high selectivity and in vivo efficacy. However, carbonyl reduction leading to the formation of the inactive hydroxyamide was identified as major metabolic liability in monkey and human, a pathway not reflected by routine absorption, distribution, metabolism, and excretion (ADME) assays. Using cytosolic clearance as a tailored in vitro ADME assay coupled with in vitro hepatocyte metabolism enabled the identification of analogues with enhanced stability against carbonyl reduction. These efforts led to the identification of P1′ modified calpain inhibitors with significantly improved pharmacokinetic profile including P1′ N-methoxyamide 23 as potential candidate compound for non-central nervous system indications.

中文翻译：

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减轻羰基还原的代谢责任：具有P1'扩展的新型钙蛋白酶抑制剂。

钙蛋白酶1和2的失调与多种病理疾病有关，包括缺血/再灌注损伤，肾脏疾病，白内障形成和神经退行性疾病，例如阿尔茨海默氏病（AD）。2-（3-苯基-1 H）-吡唑-1-基）烟酰胺代表了一系列新颖且有效的钙蛋白酶抑制剂，具有高选择性和体内功效。然而，羰基还原导致无活性羟酰胺的形成被确定为猴子和人类的主要代谢责任，这是常规吸收，分布，代谢和排泄（ADME）分析未反映的途径。使用胞浆清除率作为量身定制的体外ADME分析方法与体外方法肝细胞代谢使得能够鉴定出对羰基还原具有增强稳定性的类似物。这些努力导致鉴定出具有显着改善的药代动力学特性的P1'修饰的钙蛋白酶抑制剂，包括P1'N-甲氧基酰胺23作为非中枢神经系统适应症的潜在候选化合物。