An update on the therapeutic potential of calpain inhibitors: a patent review.

INTRODUCTION: Calpain is a cytosolic proteinase that regulates of a wide range of physiological functions. The enzyme has been implicated in various pathological conditions including neurodegenerative disorders, cardiovascular disorders, cancer, and several other diseases. Therefore, calpain inhibitors are of interest as therapeutic agents and have been studied in preclinical models of several diseases in which the enzyme has been implicated.

AREAS COVERED: Calpain inhibitors that were disclosed over the last 5 years (2015-2019) include calpastatin-based peptidomimetics; thalassospiramide lipopeptides; disulfide analogs of alpha-mercaptoacrylic acids; allosteric modulators; azoloimidazolidenones; and macrocyclic/non-macrocyclic carboxamides. The effectiveness of some of the inhibitors in preclinical animal models is discussed.

EXPERT OPINION: Significant milestones that were made over this time frame include: a) disclosure of novel blood-brain barrier (BBB) permeable calpastatin analogs as calpain inhibitors; b) disclosure that potent calpain inhibitors can be obtained by targeting the hydrophobic pockets on chain A of PEF(S) of the small subunit of calpain; c) use of PEF(S) (PDB ID: 4WQ2) in virtual screening to identify novel structurally diverse calpain inhibitors; and d) mitigation of the metabolic instability of the alpha-ketoamide warhead of calpain inhibitors.