Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, California (J.K., M.B., U.C., P.G.); and Hepion Pharmaceuticals, Edison, New Jersey (P.R.M., D.J.T., R.T.F., D.R.U.).
Department of Immunology and Microbiology, Scripps Research Institute, La Jolla, California (J.K., M.B., U.C., P.G.); and Hepion Pharmaceuticals, Edison, New Jersey (P.R.M., D.J.T., R.T.F., D.R.U.)
J Pharmacol Exp Ther. 2019 Nov;371(2):231-241. doi: 10.1124/jpet.119.261099. Epub 2019 Aug 12.
Previous studies show that cyclophilins contribute to many pathologic processes, and cyclophilin inhibitors demonstrate therapeutic activities in many experimental models. However, no drug with cyclophilin inhibition as the primary mode of action has advanced completely through clinical development to market. In this study, we present findings on the cyclophilin inhibitor, CRV431, that highlight its potential as a drug candidate for chronic liver diseases. CRV431 was found to potently inhibit all cyclophilin isoforms tested-A, B, D, and G. Inhibitory constant or IC values ranged from 1 to 7 nM, which was up to 13 times more potent than the parent compound, cyclosporine A (CsA), from which CRV431 was derived. Other CRV431 advantages over CsA as a nontransplant drug candidate were significantly diminished immunosuppressive activity, less drug transporter inhibition, and reduced cytotoxicity potential. Oral dosing to mice and rats led to good blood exposures and a 5- to 15-fold accumulation of CRV431 in liver compared with blood concentrations across a wide range of CRV431 dosing levels. Most importantly, CRV431 decreased liver fibrosis in a 6-week carbon tetrachloride model and in a mouse model of nonalcoholic steatohepatitis (NASH). Additionally, CRV431 administration during a late, oncogenic stage of the NASH disease model resulted in a 50% reduction in the number and size of liver tumors. These findings are consistent with CRV431 targeting fibrosis and cancer through multiple, cyclophilin-mediated mechanisms and support the development of CRV431 as a safe and effective drug candidate for liver diseases. SIGNIFICANCE STATEMENT: Cyclophilin inhibitors have demonstrated therapeutic activities in many disease models, but no drug candidates have yet advanced completely through development to market. In this study, CRV431 is shown to potently inhibit multiple cyclophilin isoforms, possess several optimized pharmacological properties, and decrease liver fibrosis and tumors in mouse models of chronic liver disease, which highlights its potential to be the first approved drug primarily targeting cyclophilin isomerases.
先前的研究表明亲环素参与了许多病理过程，并且亲环素抑制剂在许多实验模型中表现出了治疗活性。然而，作为主要作用模式的亲环素抑制剂类药物，没有一种完全通过临床开发进入市场。在这项研究中，我们介绍了亲环素抑制剂 CRV431 的研究结果，突出了其作为慢性肝病候选药物的潜力。CRV431 被发现能强烈抑制所有测试的亲环素同工酶-A、B、D 和 G。抑制常数（IC）值范围为 1 至 7 nM，比其母体化合物环孢素 A（CsA）的效力高 13 倍，CRV431 就是从 CsA 衍生而来。与 CsA 作为非移植候选药物相比，CRV431 还有其他优势，包括免疫抑制活性显著降低、药物转运体抑制作用更小、细胞毒性潜力降低。对小鼠和大鼠进行口服给药后，在广泛的 CRV431 给药水平下，其在血液中的暴露水平良好，并且在肝脏中的积累是血液浓度的 5 至 15 倍。最重要的是，CRV431 可减少 6 周的四氯化碳模型和非酒精性脂肪性肝炎（NASH）小鼠模型中的肝纤维化。此外，在 NASH 疾病模型的晚期致癌阶段给予 CRV431 可使肝脏肿瘤的数量和大小减少 50%。这些发现与 CRV431 通过多种亲环素介导的机制靶向纤维化和癌症的作用一致，并支持 CRV431 作为一种安全有效的肝脏疾病候选药物的开发。意义：亲环素抑制剂在许多疾病模型中表现出了治疗活性，但没有候选药物完全通过开发进入市场。在这项研究中，CRV431 被证明能强烈抑制多种亲环素同工酶，具有多种优化的药理学特性，并可减少慢性肝病小鼠模型中的肝纤维化和肿瘤，这突出了其作为首个主要针对亲环素异构酶的获批药物的潜力。
