2. Academic Validation
  3. 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

  • 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

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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