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

ABSTRACT

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.

KEYWORDS:

• Alpha-mercaptoacrylic acids
• Alzheimer’s disease
• azoloimidazolidenones
• calpain inhibitors
• calpastatin
• carboxamides
• nonpeptide
• Parkinson’s disease
• peptidomimetics
• thalassospiramides

Article Highlights

• Design of peptidomimetic compounds that incorporate the conserved β-turn residues of calpastatin

• Discovery of BBB permeable peptidomimetics based on the 27-mer calpastatin peptide.

• Disclosure of disulfide analogues of alpha-mercaptoacrylic acids as potent inhibitors of calpain.

• Discovery of allosteric inhibitors via virtual screening of compound libraries [68]. Mitigation of the metabolic instability of the carbonyl group of the alpha-ketoamide warhead of calpain inhibitors

Declaration of interest

The author has no relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.