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

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posted on 31.07.2017, 00:00 by Andreas Kling, Katja Jantos, Helmut Mack, Wilfried Hornberger, Karla Drescher, Volker Nimmrich, Ana Relo, Karsten Wicke, Charles W. Hutchins, Yanbin Lao, Kennan Marsh, Achim Moeller
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.