Inhibitors of HIV-1 attachment. Part 9: An assessment of oral prodrug approaches to improve the plasma exposure of a tetrazole-containing derivative

被引：30

作者：

Yeung, Kap-Sun ^{[1
]}

Qiu, Zhilei ^{[1
]}

Yang, Zheng ^{[1
]}

Zadjura, Lisa ^{[1
]}

D'Arienzo, Celia J. ^{[1
]}

Browning, Marc R. ^{[1
]}

Hansel, Steven ^{[1
]}

Huang, Xiaohua Stella ^{[1
]}

Eggers, Betsy J. ^{[1
]}

Riccardi, Keith ^{[1
]}

Lin, Ping-Fang ^{[1
]}

Meanwell, Nicholas A. ^{[1
]}

Kadow, John F. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Res & Dev, Wallingford, CT 06492 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 01期

关键词：

Antivirals; HIV-1 attachment inhibitors; Indole glyoxamide; Tetrazole; Produrgs; II RECEPTOR ANTAGONISTS; SUBSTITUTION PATTERNS; DISCOVERY; METABOLISM; ENVELOPE; BINDING; DESIGN; ENTRY; ACIDS;

D O I：

10.1016/j.bmcl.2012.10.125

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

7-(2H-Tetrazol-5-yl)-1H-indole 3 was found to be a potent inhibitor of HIV-1 attachment but the compound lacked oral bioavailability in rats. The cause of the low exposure was believed to be poor absorption attributed to the acidic nature of the tetrazole moiety and, in an effort to address this liability, three more lipohilic tetrazole analogs, N-acetoxymethyl 4, N-pivaloyloxymethyl 5, and N-methyl 6, were evaluated as potential oral prodrugs in rats. Prodrug 5 was ineffective in improving the plasma concentration of 3 in vivo but compound 4 provided a 15-fold enhancement of the plasma concentration of 3. Most interestingly, oral dosing of analog 6 afforded a substantial increase in the plasma concentration of the parent in rats when compared to dosing of parent. This represents a novel example of a methyl tetrazole that acts as a prodrug for a free NH tetrazole-containing compound. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：209 / 212

页数：4

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