细胞色素P450（CYP）3A新型药物增强剂二胺抑制剂的构效关系。第二部分：P2/P3区域与考比司他（GS-9350）的发现
Structure-activity relationships of diamine inhibitors of cytochrome P450 (CYP) 3A as novel pharmacoenhancers. Part II: P2/P3 region and discovery of cobicistat (GS-9350).
作者信息
Xu Lianhong, Liu Hongtao, Hong Allen, Vivian Randy, Murray Bernard P, Callebaut Christian, Choi You-Chul, Lee Melody S, Chau Jennifer, Tsai Luong K, Stray Kirsten M, Strickley Robert G, Wang Jianhong, Tong Leah, Swaminathan Swami, Rhodes Gerry R, Desai Manoj C
机构信息
Department of Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
Department of Medicinal Chemistry, Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94303, USA.
出版信息
Bioorg Med Chem Lett. 2014 Feb 1;24(3):995-9. doi: 10.1016/j.bmcl.2013.12.057. Epub 2013 Dec 21.
The HIV protease inhibitor (PI) ritonavir (RTV) has been widely used as a pharmacoenhancer for other PIs, which are substrates of cytochrome P450 3A (CYP3A). However the potent anti-HIV activity of ritonavir may limit its use as a pharmacoenhancer with other classes of anti-HIV agents. Ritonavir is also associated with limitations such as poor physicochemical properties. To address these issues a series of compounds with replacements at the P2 and/or P3 region was designed and evaluated as novel CYP3A inhibitors. Through these efforts, a potent and selective inhibitor of CYP3A, GS-9350 (cobicistat) with improved physiochemical properties was discovered.
人类免疫缺陷病毒蛋白酶抑制剂（PI）利托那韦（RTV）已被广泛用作其他PI的药物增强剂，这些PI是细胞色素P450 3A（CYP3A）的底物。然而，利托那韦强大的抗HIV活性可能会限制其作为其他抗HIV药物类别之药物增强剂的用途。利托那韦还存在诸如物理化学性质不佳等局限性。为解决这些问题，设计了一系列在P2和/或P3区域有取代基的化合物，并将其作为新型CYP3A抑制剂进行评估。通过这些努力，发现了一种具有改善物理化学性质的强效且选择性的CYP3A抑制剂GS-9350（考比司他）。
Zotero 插件