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. Epub 2019 May 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Glycoproteins / pharmacology
  • Glycoproteins / therapeutic use*
  • Humans
  • Pyrrolidines / metabolism*
  • Structure-Activity Relationship

Substances

  • Glycoproteins
  • Pyrrolidines
  • calpain inhibitors
  • alicapistat