Synthesis of α-Ketoamide-Based Stereoselective Calpain-1 Inhibitors as Neuroprotective Agents.

Abstract

Calpain inhibitors have been proposed as drug candidates for neurodegenerative disorders, with ABT-957 entering clinical trials for Alzheimer's disease and mild cognitive impairment. The structure of ABT-957 was very recently disclosed, and trials were terminated owing to inadequate CNS concentrations to obtain a pharmacodynamic effect. The multistep synthesis of an α-ketoamide peptidomimetic inhibitor series potentially including ABT-957 was optimized to yield diastereomerically pure compounds that are potent and selective for calpain-1 over papain and cathepsins B and K. As the final oxidation step, with its optimized synthesis protocol, does not alter the configuration of the substrate, the synthesis of the diastereomeric pair (R)-1-benzyl-N-((S)-4-((4-fluorobenzyl)amino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide (1 c) and (R)-1-benzyl-N-((R)-4-((4-fluorobenzyl)amino)-3,4-dioxo-1-phenylbutan-2-yl)-5-oxopyrrolidine-2-carboxamide (1 g) was feasible. This allowed the exploration of stereoselective inhibition of calpain-1, with 1 c (IC50 =78 nM) being significantly more potent than 1 g. Moreover, inhibitor 1 c restored cognitive function in amnestic mice.

• Authors: Ammar Jastaniah, Irina N Gaisina, Rachel C Knopp, Gregory R J Thatcher
• Journal: ChemMedChem (ChemMedChem) Vol. 15 Issue 23 Pg. 2280-2285 (12 03 2020) ISSN: 1860-7187 [Electronic] Germany
• PMID: 32840034 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Wiley-VCH GmbH.

Chemical References

• Glycoproteins
• Neuroprotective Agents
• Pyrrolidines
• calpain inhibitors
• alicapistat
• Scopolamine
• Calpain
• CAPNS1 protein, human

Topics

• Amnesia (chemically induced, drug therapy, metabolism)
• Animals
• Calpain (antagonists & inhibitors, metabolism)
• Glycoproteins (chemical synthesis, chemistry, pharmacology)
• Mice
• Molecular Structure
• Neuroprotective Agents (chemical synthesis, chemistry, pharmacology)
• Pyrrolidines (chemical synthesis, chemistry, pharmacology)
• Scopolamine
• Stereoisomerism