Journal of Medicinal Chemistry
Journal of Medicinal Chemistry
5 years ago

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

Discovery of Novel and Highly Selective Inhibitors of Calpain for the Treatment of Alzheimer’s Disease: 2-(3-Phenyl-1H-pyrazol-1-yl)-nicotinamides
Yanbin Lao, Kennan Marsh, Ana Relo, Volker Nimmrich, Andreas Kling, Achim Moeller, Wilfried Hornberger, Karsten Wicke, Karla Drescher, Helmut Mack, Charles W. Hutchins, Katja Jantos
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.

Publisher URL: http://dx.doi.org/10.1021/acs.jmedchem.7b00731

DOI: 10.1021/acs.jmedchem.7b00731

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