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用于治疗阿尔茨海默病的新型高选择性钙蛋白酶抑制剂的发现：2-(3-苯基-1H-吡唑-1-基)-烟酰胺

Discovery of Novel and Highly Selective Inhibitors of Calpain for the Treatment of Alzheimer's Disease: 2-(3-Phenyl-1H-pyrazol-1-yl)-nicotinamides.

作者信息

Kling Andreas, Jantos Katja, Mack Helmut, Hornberger Wilfried, Drescher Karla, Nimmrich Volker, Relo Ana, Wicke Karsten, Hutchins Charles W, Lao Yanbin, Marsh Kennan, Moeller Achim

机构信息

Neuroscience Research, AbbVie Deutschland GmbH & Co. KG , Knollstrasse, 67061 Ludwigshafen, Germany.

AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064-6125, United States.

出版信息

J Med Chem. 2017 Aug 24;60(16):7123-7138. doi: 10.1021/acs.jmedchem.7b00731. Epub 2017 Aug 15.

DOI:10.1021/acs.jmedchem.7b00731
PMID:28759231
Abstract

Calpain overactivation has been implicated in a variety of pathological disorders including ischemia/reperfusion injury, cataract formation, and neurodegenerative diseases such as Alzheimer's disease (AD). Herein we describe our efforts leading to the identification of ketoamide-based 2-(3-phenyl-1H-pyrazol-1-yl)nicotinamides as potent and reversible inhibitors of calpain with high selectivity versus related cysteine protease cathepsins, other proteases, and receptors. Broad efficacy in a set of preclinical models relevant to AD suggests that inhibition of calpain represents an attractive approach with potential benefit for the treatment of AD.

摘要

钙蛋白酶过度激活与多种病理疾病有关，包括缺血/再灌注损伤、白内障形成以及神经退行性疾病如阿尔茨海默病（AD）。在此，我们描述了我们的研究工作，这些工作导致了基于酮酰胺的2-(3-苯基-1H-吡唑-1-基)烟酰胺的鉴定，该化合物是钙蛋白酶的有效且可逆的抑制剂，对相关半胱氨酸蛋白酶组织蛋白酶、其他蛋白酶和受体具有高选择性。在一组与AD相关的临床前模型中的广泛疗效表明，抑制钙蛋白酶是一种有吸引力的方法，对AD的治疗可能有益。

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