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)-1benzyl-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 (IC 50 = 78 nM) being significantly more potent than 1 g. Moreover, inhibitor 1 c restored cognitive function in amnestic mice.

Extending the Calpain–Cathepsin Hypothesis to the Neurovasculature: Protection of Brain Endothelial Cells and Mice from Neurotrauma

“…We pursued a series of ketoamides based upon published patents and computational docking studies . Of this series of compounds, 1 – 5 were observed to be potent and highly selective toward calpain-1 at 1 μM with minimal inhibitory activity against cathepsin-B, papain, and cathepsin-K (Figure B,C; Table S1).…”

“…53 AbbVie have used amnesia induced by the muscarininc Ach-receptor blocker scopolamine in preclinical development of calpain inhibitors; we have shown 5 and a nonselective calpain inhibitor to be effective in this assay. 30 However, neither REM sleep nor scopolamine-induced amnesia provide a test of the calpain−cathepsin hypothesis.…”

“…NYC-438, 5, and E64d were synthesized and characterized according to the literature. 30,32 Animals. All animal care and procedures were conducted with approved institutional animal care protocols and in accordance with the NIH Guide for the Care and Use of Laboratory Animals.…”

The Alpha Keto Amide Moiety as a Privileged Motif in Medicinal Chemistry: Current Insights and Emerging Opportunities

“… Binding of 119 (A) and 140 (B) in the active site of calpain-1. 206 Reproduced with permission from ref ( 206 ). Copyright 2020 Wiley-VCH GmbH.…”

Calpain‐1 mediates vascular remodelling and fibrosis via HIF‐1α in hypoxia‐induced pulmonary hypertension

“…Growing studies have shown that calpain is involved in many diseases, including cardiovascular diseases, cancer, neurodegenerative diseases and several other diseases. [20][21][22][23][24] Consistent with previous studies, 9 our results showed that hypoxia elevated calpain-1 protein levels in both lung tissues of mice with HPH and PASMCs, significantly increased RVSP, right ventricular hypertrophy and vessel wall thickness, increased the expression of PCNA, Ki-67, α-SMA and the formation of collagen fibre in the lung tissues, and enhanced the It has been reported that calpain-1 is involved in the formation of fibrosis by regulating the expression of angiopoietin-1, IL-6, MMP2, collagen I and III. Besides, calpain-1 overexpression can also induce activation of TGF-β1/Smad signalling pathway in vascular smooth muscle cells.…”