Synthesis of α‐Ketoamide‐Based Stereoselective Calpain‐1 Inhibitors as Neuroprotective Agents. (18th September 2020)

• Record Type: Journal Article
• Authors: Jastaniah, Ammar; Gaisina, Irina N.; Knopp, Rachel C.; Thatcher, Gregory R. J.
• Is Part Of: ChemMedChem. Volume 15:Number 23(2020)
• Page Start: 2280
• Page End: 2285
• Publication Date: 2020-09-18
• Subjects: calpain -- chirality -- cysteine proteases -- alpha-ketoamides -- peptidomimetics; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000385
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Abstract : Don't forget : ( R )‐1‐Benzyl‐ N ‐(( S )‐4‐((4‐fluorobenzyl)amino)‐3, 4‐dioxo‐1‐phenylbutan‐2‐yl)‐5‐oxopyrrolidine‐2‐carboxamide (1 c ) is a potent and selective calpain‐1 inhibitor (IC50 =78 nM) that restored memory in response to the blockade of cholinergic signaling by the mAChR antagonist scopolamine.