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

  • J Med Chem. 2017 Aug 24;60(16):7123-7138. doi: 10.1021/acs.jmedchem.7b00731.
Andreas Kling  1 ,  Katja Jantos  1 ,  Helmut Mack  1 ,  Wilfried Hornberger  1 ,  Karla Drescher  1 ,  Volker Nimmrich  1 ,  Ana Relo  1 ,  Karsten Wicke  1 ,  Charles W Hutchins  2 ,  Yanbin Lao  2 ,  Kennan Marsh  2 ,  Achim Moeller  1
Affiliations
  • 1. Neuroscience Research, AbbVie Deutschland GmbH & Co. KG , Knollstrasse, 67061 Ludwigshafen, Germany.
  • 2. AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064-6125, United States.
PMID: 28759231 DOI: 10.1021/acs.jmedchem.7b00731
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.

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