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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease / drug therapy*
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Aminobutyrates / chemical synthesis
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Aminobutyrates / pharmacokinetics
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Aminobutyrates / pharmacology*
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Animals
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Calpain / antagonists & inhibitors*
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Cathepsins
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Cysteine Proteinase Inhibitors / chemical synthesis
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Cysteine Proteinase Inhibitors / pharmacokinetics
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Cysteine Proteinase Inhibitors / pharmacology*
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Dogs
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Hippocampus / metabolism
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Humans
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Inhibitory Concentration 50
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Macaca fascicularis
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Male
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Microsomes, Liver / metabolism
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Niacinamide / analogs & derivatives*
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Niacinamide / chemical synthesis
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Niacinamide / pharmacokinetics
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Niacinamide / pharmacology*
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Pyrazoles / chemical synthesis
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Pyrazoles / pharmacokinetics
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Pyrazoles / pharmacology*
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Rats, Inbred F344
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Rats, Sprague-Dawley
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Rats, Wistar
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Sleep, REM / drug effects
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Spectrin / metabolism
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Stereoisomerism
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Structure-Activity Relationship
Substances
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A-933548
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Aminobutyrates
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Cysteine Proteinase Inhibitors
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Pyrazoles
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Spectrin
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Niacinamide
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Cathepsins
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Calpain
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CAPN1 protein, human