Discovery of Novel and Highly Selective Inhibitors of Calpain for the Treatment of Alzheimer’s Disease: 2-(3-Phenyl-1H-pyrazol-1-yl)-nicotinamides
2017
Calpainoveractivation 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)
nicotinamidesas potent and reversible inhibitors of
calpainwith 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
calpainrepresents an attractive approach with potential benefit for the treatment of AD.
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