Potent Nonimmunosuppressive Cyclophilin Inhibitors With Improved Pharmaceutical Properties and Decreased Transporter Inhibition
Potent Nonimmunosuppressive Cyclophilin Inhibitors With Improved Pharmaceutical Properties and Decreased Transporter Inhibition
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DOI：
10.1021/jm500862r
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发表时间：
2014-10-23
影响因子：
7.3
通讯作者：
Sweeney, Zachary K.
中科院分区：
文献类型：
--
作者：
Fu, Jiping;Tjandra, Meiliana;Sweeney, Zachary K.
非免疫抑制亲环素抑制剂已被证明是治疗丙型肝炎感染(丙型肝炎)的有效药物。然而，阿利斯匹韦、环孢菌素A和大多数其他环孢菌素是OATP1B1、MRP2、MDR1和其他重要药物转运蛋白的有效抑制剂。P4残基侧链疏水性的降低保留了亲环素结合和抗病毒的效力，同时减少了转运蛋白的抑制。代表性抑制剂33(NIM258)是一种与先前描述的环孢菌素相比效力较弱的转运蛋白抑制剂，在细胞培养中保持抗丙型肝炎病毒的活性，并在大鼠和狗身上具有可接受的药动学特征。报道了与大鼠亲环素D结合的33的X射线结构。
Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.