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J Med Chem. 2003 Jun 5;46(12):2404-12.

Benzoylalanine-derived ketoamides carrying vinylbenzyl amino residues: discovery of potent water-soluble calpain inhibitors with oral bioavailability.

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  • 1Neuroscience Discovery Research, Abbott GmbH & Co. KG, P.O. Box 210805, D-67008 Ludwigshafen, Germany.


Novel benzoylalanine-derived ketoamides were prepared and evaluated for calpain I inhibition. Derivatives carrying vinylbenzyl amino residues in the P(2)-P(3) region inhibited calpain in nanomolar concentrations and thus represent a novel class of nonpeptidic calpain inhibitors. Selected examples exhibited an improved pharmacokinetic profile including improved water-solubility and metabolic stability. In particular, these calpain inhibitors showed oral bioavailability in rats as demonstrated by N-(1-benzyl-2-carbamoyl-2-oxoethyl)-2-[E-2-(4-diethylaminomethylphenyl)ethen-1-yl]benzamide (5d). The closely related derivative N-(1-carbamoyl-1-oxohex-1-yl)-2-[E-2-(4-dimethylaminomethylphenyl)-ethen-1-yl]benzamide (5b) was evaluated for neuroprotective efficacy after experimental traumatic brain injury in a fluid percussion model in rats. When administered after injury, 5b reduced the number of damaged neurons by 41%, and this result would be in line with the suggested neuroprotective efficacy of calpain inhibition.

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