Discovery and optimization of pyridazinone non-nucleoside inhibitors of HIV-1 reverse transcriptase

被引：44

作者：

Sweeney, Zachary K. ^{[1
]}

Dunn, James P. ^{[1
]}

Li, Yu ^{[1
]}

Heilek, Gabrielle ^{[1
]}

Dunten, Pete ^{[1
]}

Elworthy, Todd R. ^{[1
]}

Han, Xiaochun ^{[1
]}

Harris, Seth F. ^{[1
]}

Hirschfeld, Donald R. ^{[1
]}

Hogg, J. Heather ^{[1
]}

Huber, Walter ^{[2
]}

Kaiser, Ann C. ^{[1
]}

Kertesz, Denis J. ^{[1
]}

Kim, Woongki ^{[1
]}

Mirzadegan, Taraneh ^{[1
]}

Roepel, Michael G. ^{[1
]}

Saito, Y. David ^{[1
]}

Silva, Tania M. P. C. ^{[1
]}

Swallow, Steven ^{[1
]}

Tracy, Jahari L. ^{[1
]}

Villasenor, Armando ^{[1
]}

Vora, Harit ^{[1
]}

Zhou, Amy S. ^{[1
]}

Klumpp, Klaus ^{[1
]}

机构：

[1] Roche Palo Alto LLC, Palo Alto, CA 94304 USA

[2] F Hoffmann La Roche & Co Ltd, CH-4002 Basel, Switzerland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 15期

关键词：

human immunodeficiency virus; HIV; NNRTI; non-nucleoside; reverse transcriptase;

D O I：

10.1016/j.bmcl.2008.06.072

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of benzyl pyridazinones were evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Several members of this series showed good activity against the wild-type virus and NNRTI-resistant viruses. The binding of inhibitor 5a to HIV-RT was analyzed by surface plasmon resonance spectroscopy. Pharmacokinetic studies of 5a in rat and dog demonstrated that this compound has good oral bioavailability in animal species. The crystal structure of a complex between HIV-RT and inhibitor 4c is also described. (c) 2008 Elsevier Ltd. All rights reserved.

引用

收藏

页码：4352 / 4354

页数：3

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