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)
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- 作者：Lianhong Xu ; Hongtao Liu ; Allen Hong ; R ; y Vivian ; Bernard P. Murray ; Christian Callebaut ; You-Chul Choi ; Melody S. Lee ; Jennifer Chau ; Luong K. Tsai ; Kirsten M. Stray ; Robert G. Strickley ; Jianhong Wang ; Leah Tong ; Swami Swaminathan ; Gerry R. Rhodes ; Manoj C. Desai
- 关键词：CYP3A inhibitors ; 1 ; 4-Diamines ; Pharmacoenhancer ; Selectivity against different CYP enzymes
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：1 February, 2014
- 年：2014
- 卷：24
- 期：3
- 页码：995-999
- 全文大小：3526 K
文摘
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.