1. 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
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Kling A, Jantos K, Mack H, Hornberger W, Drescher K, Nimmrich V, Relo A, Wicke K, Hutchins CW, Lao Y, Marsh K, and Moeller A
- Subjects
- Aminobutyrates chemical synthesis, Aminobutyrates pharmacokinetics, Animals, Cathepsins, Cysteine Proteinase Inhibitors chemical synthesis, Cysteine Proteinase Inhibitors pharmacokinetics, Dogs, Hippocampus metabolism, Humans, Inhibitory Concentration 50, Macaca fascicularis, Male, Microsomes, Liver metabolism, Niacinamide chemical synthesis, Niacinamide pharmacokinetics, Pyrazoles chemical synthesis, Pyrazoles pharmacokinetics, Rats, Inbred F344, Rats, Sprague-Dawley, Rats, Wistar, Sleep, REM drug effects, Spectrin metabolism, Stereoisomerism, Structure-Activity Relationship, Alzheimer Disease drug therapy, Aminobutyrates pharmacology, Calpain antagonists & inhibitors, Cysteine Proteinase Inhibitors pharmacology, Niacinamide analogs & derivatives, Niacinamide pharmacology, Pyrazoles pharmacology
- 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.
- Published
- 2017
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