Structure-activity relationships of diamine inhibitors of cytochrome P450 (CYP) 3A as novel pharmacoenhancers, part I: Core region

被引：10

作者：

Liu, Hongtao ^{[1
]}

Xu, Lianhong ^{[1
]}

Hui, Hon ^{[1
]}

Vivian, Randy ^{[1
]}

Callebaut, Christian ^{[3
]}

Murray, Bernard P. ^{[2
]}

Hong, Allen ^{[1
]}

Lee, Melody S. ^{[2
]}

Tsai, Luong K. ^{[3
]}

Chau, Jennifer K. ^{[2
]}

Stray, Kirsten M. ^{[3
]}

Cannizzaro, Carina ^{[4
]}

Choi, You-Chul ^{[1
]}

Rhodes, Gerry R. ^{[2
]}

Desai, Manoj C. ^{[1
]}

机构：

[1] Gilead Sci Inc, Dept Med Chem, Foster City, CA 94404 USA

[2] Gilead Sci Inc, Dept Drug Metab, Foster City, CA 94404 USA

[3] Gilead Sci Inc, Dept Biol, Foster City, CA 94404 USA

[4] Gilead Sci Inc, Dept Struct Chem, Foster City, CA 94404 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 03期

关键词：

CYP3A inhibitors; HIV-1 protease inhibitors; 1,4-Diamines; Pharmacoenhancer Selectivity against different CYP enzymes; IMMUNODEFICIENCY-VIRUS PROTEASE; DRUG-INTERACTIONS; RITONAVIR; PHARMACOKINETICS; ENHANCEMENT; INDUCTION; THERAPY; POTENT;

D O I：

10.1016/j.bmcl.2013.12.058

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Ritonavir (RTV), an HIV-1 protease inhibitor (PI), is also a potent mechanism-based inhibitor of human cytochrome P450 3A (CYP3A) and has been widely prescribed as a pharmacoenhancer. As a boosting agent for marketed PIs, it reduces pill burden, and improves compliance. Removal of the hydroxyl group from RTV reduces, but does not eliminate HIV PI activity and does not affect CYP3A inhibition. Herein we report the discovery of a novel series of CYP3A inhibitors that are devoid of antiviral activity. The synthesis and evaluation of analogs with extensive modifications of the 1,4-diamine core along with the structure activity relationships with respect to anti-HIV activity, CYP3A inhibitory activity, selectivity against other CYP enzymes and the human pregnane X receptor (PXR) will be discussed. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：989 / 994

页数：6

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