The University of Tennessee Health Science Center, College of Pharmacy, Department of Pharmaceutical Sciences, 847 Monroe Avenue, 327E Johnson Building, Memphis, TN 38163, USA.
Expert Opin Ther Pat. 2011 May;21(5):601-36. doi: 10.1517/13543776.2011.568480. Epub 2011 Mar 24.
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.
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.
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.
钙蛋白酶是一种半胱氨酸蛋白酶，参与正常的信号转导事件，但它的作用失调可能导致神经紊乱、肌肉萎缩症、白内障、癌症和糖尿病等疾病。在这些疾病的动物模型中，钙蛋白酶的抑制作用被证明是有益的；因此，该酶已被提议作为一个潜在的药物靶点。
本文对过去十年（2001-2010 年）专利和科学文献中报道的钙蛋白酶抑制剂进行了全面综述。讨论了具有和不具有反应性弹头的肽、肽模拟物和非肽抑制剂。还讨论了提高肽钙蛋白酶抑制剂细胞摄取率、改善抑制剂的药代动力学特性和钙蛋白酶抑制剂的特异性靶向的进展。
钙蛋白酶抑制剂在与钙蛋白酶相关的疾病的动物模型中显示出疗效，但由于缺乏钙蛋白酶同工型选择性和抑制剂的一般反应性，抑制剂进入临床试验受到了阻碍。因此，应努力寻找没有这些问题的化合物。探索与酶的变构位点结合的化合物可能会规避这些问题，并提供新的药物线索。
