Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1

被引：136

作者：

Fader, Lee D. ^{[1
]}

Malenfant, Eric ^{[1
]}

Parisien, Mathieu ^{[1
]}

Carson, Rebekah ^{[1
]}

Bilodeau, Francois ^{[1
]}

Landry, Serge ^{[1
]}

Pesant, Marc ^{[1
]}

Brochu, Christian ^{[1
]}

Morin, Sebastien ^{[1
]}

Chabot, Catherine ^{[1
]}

Halmos, Ted ^{[1
]}

Bousquet, Yves ^{[1
]}

Bailey, Murray D. ^{[1
]}

Kawai, Stephen H. ^{[1
]}

Coulombe, Rene ^{[1
]}

LaPlante, Steven ^{[1
]}

Jakalian, Araz ^{[1
]}

Bhardwaj, Punit K. ^{[1
]}

Wernic, Dominik ^{[1
]}

Schroeder, Patricia ^{[1
]}

Amad, Ma'an ^{[1
]}

Edwards, Paul ^{[1
]}

Garneau, Michel ^{[1
]}

Duan, Jianmin ^{[1
]}

Cordingley, Michael ^{[1
]}

Bethell, Richard ^{[1
]}

Mason, Stephen W. ^{[1
]}

Boes, Michael ^{[1
]}

Bonneau, Pierre ^{[1
]}

Poupart, Marc-Andre ^{[1
]}

Faucher, Anne-Marie ^{[1
]}

Simoneau, Bruno ^{[1
]}

Fenwick, Craig ^{[1
]}

Yoakim, Christiane ^{[1
]}

Tsantrizos, Youla ^{[1
]}

机构：

[1] Boehringer Ingelheim Canada Ltd, Res & Dev, Laval, PQ H7S 2G5, Canada

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2014年 / 5卷 / 04期

关键词：

HIV Integrase; allosteric inhibitor; LTR DNA 3 '-processing; NCINI; SMALL-MOLECULE INHIBITORS; BINDING-SITE; IDENTIFICATION; LEDGF/P75; MECHANISM; ERA;

D O I：

10.1021/ml500002n

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

An assay recapitulating the 3' processing activity of HIV-1 integrase (IN) was used to screen the Boehringer Ingelheim compound collection. Hit-to-lead and lead optimization beginning with compound 1 established the importance of the C3 and C4 substituent to antiviral potency against viruses with different aa124/aa125 variants of IN. The importance of the C7 position on the serum shifted potency was established. Introduction of a quinoline substituent at the C4 position provided a balance of potency and metabolic stability. Combination of these findings ultimately led to the discovery of compound 26 (BI 224436), the first NCINI to advance into a phase Ia clinical trial.

引用

页码：422 / 427

页数：6

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