Calpain inhibitors: a survey of compounds reported in the patent and scientific literature

Abstract

Introduction: Calpain is a cysteine protease that participates in normal signal transduction events, but deregulation of its action may result in pathologies such as neurological disorders, muscular dystrophies, cataract, cancer and diabetes. Inhibition of calpain is demonstrably beneficial in animal models of these diseases; hence, the enzyme has been proposed as a potential drug target.

Areas covered: A comprehensive review of calpain inhibitors reported in the patent and scientific literature over the past decade (2001 – 2010) is presented in this paper. Peptides, peptidomimetics and nonpeptide inhibitors with and without reactive warheads are discussed. Advances made in enhancing the cellular uptake of peptide calpain inhibitors, improving the pharmacokinetic properties of the inhibitors and site specific targeting of calpain inhibitors are also discussed.

Expert opinion: Calpain inhibitors have demonstrated efficacy in animal models of calpain related diseases, but progression of the inhibitors into clinical trials has been hampered partly due to lack of calpain isoform selectivity and the general reactivity of the inhibitors. Therefore, efforts should be directed towards the discovery of compounds devoid of these problems. Exploration of compounds that bind to allosteric sites of the enzyme may circumvent these problems and afford new drug leads.

Keywords::

• calpain
• calpastatin
• nonpeptide
• peptidomimetic
• pharmacokinetics
• subsites