Discovery of ABT-957: 1-Benzyl-5-oxopyrrolidine-2-carboxamides as selective calpain inhibitors with enhanced metabolic stability

[Display omitted] Aberrant activation of calpain has been observed in various pathophysiological disorders including neurodegenerative diseases such as Alzheimer’s Disease. Here we describe our efforts on ketoamide-based 1-benzyl-5-oxopyrrolidine-2-carboxamides as a novel series of highly selective...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2019-08, Vol.29 (15), p.1968-1973
Hauptverfasser:	Jantos, Katja, Kling, Andreas, Mack, Helmut, Hornberger, Wilfried, Moeller, Achim, Nimmrich, Volker, Lao, Yanbin, Nijsen, Marjoleen
Format:	Artikel
Sprache:	eng
Schlagworte:	Alzheimer’s Disease Calpain inhibition Cysteine protease inhibition Ketoamide
Online-Zugang:	Volltext
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Zusammenfassung:	[Display omitted] Aberrant activation of calpain has been observed in various pathophysiological disorders including neurodegenerative diseases such as Alzheimer’s Disease. Here we describe our efforts on ketoamide-based 1-benzyl-5-oxopyrrolidine-2-carboxamides as a novel series of highly selective calpain inhibitors mitigating the metabolic liability of carbonyl reduction. The most advanced compound from this new series, namely A-1212805 (ABT-957, Alicapistat) proceeded to clinical phase I studies.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2019.05.034