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

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.

DOI: 10.1021/acs.jmedchem.7b00731

Cite this paper

@article{Kling2017DiscoveryON, title={Discovery of Novel and Highly Selective Inhibitors of Calpain for the Treatment of Alzheimer's Disease: 2-(3-Phenyl-1H-pyrazol-1-yl)-nicotinamides.}, author={Andreas Kling and Katja Jantos and Helmut Mack and Wilfried B Hornberger and Karla U. Drescher and Volker Nimmrich and Ana L Relo and Karsten M. Wicke and Charles Hutchins and Yanbin Lao and Kennan C. Marsh and Achim Moeller}, journal={Journal of medicinal chemistry}, year={2017}, volume={60 16}, pages={7123-7138} }