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

  • Bioorg Med Chem Lett. 2019 Aug 1;29(15):1968-1973. doi: 10.1016/j.bmcl.2019.05.034.
Katja Jantos  1 ,  Andreas Kling  2 ,  Helmut Mack  3 ,  Wilfried Hornberger  3 ,  Achim Moeller  3 ,  Volker Nimmrich  4 ,  Yanbin Lao  5 ,  Marjoleen Nijsen  5
Affiliations
  • 1. AbbVie Deutschland GmbH & Co. KG, Neuroscience Research, Knollstrasse, 67061 Ludwigshafen, Germany. Electronic address: [email protected].
  • 2. AbbVie Deutschland GmbH & Co. KG, Neuroscience Research, Knollstrasse, 67061 Ludwigshafen, Germany. Electronic address: [email protected].
  • 3. AbbVie Deutschland GmbH & Co. KG, Neuroscience Research, Knollstrasse, 67061 Ludwigshafen, Germany.
  • 4. AbbVie Deutschland GmbH & Co. KG, DMPK-BA, Knollstrasse, 67061 Ludwigshafen, Germany.
  • 5. AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064-6125, United States.
PMID: 31133534 DOI: 10.1016/j.bmcl.2019.05.034
Abstract

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.

Keywords
Alzheimer’s Disease; Calpain inhibition; Cysteine protease inhibition; Ketoamide.
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