Discovery of Potent, Orally Bioavailable Inhibitors of Human Cytomegalovirus

被引：4

作者：

Fader, Lee ^{[1
,2
]}

Brault, Martine ^{[1
]}

Desjardins, Jessica ^{[1
]}

Dansereau, Nathalie ^{[1
]}

Lamorte, Louie ^{[1
]}

Tremblay, Sonia ^{[1
]}

Bilodeau, Francois ^{[1
]}

Bordeleau, Josee ^{[1
]}

Duplessis, Martin ^{[1
]}

Gorys, Vida ^{[1
]}

Gillard, James ^{[1
]}

Gleason, James L. ^{[1
]}

James, Clint ^{[1
]}

Joly, Marc-Andre ^{[1
]}

Kuhn, Cyrille ^{[1
]}

Llinas-Brunet, Montse ^{[1
]}

Luo, Laibin ^{[1
]}

Morency, Louis ^{[1
]}

Morin, Sebastien ^{[1
]}

Parisien, Mathieu ^{[1
]}

Poirier, Maude ^{[1
]}

Thibeault, Carl ^{[1
]}

Thao Trinh ^{[1
]}

Sturino, Claudio ^{[1
]}

Srivastava, Sanjay ^{[1
]}

Yoakim, Christiane ^{[1
]}

Franti, Michael ^{[1
,2
]}

机构：

[1] Boehringer Ingelheim Canada Ltd, Res & Dev, 2100 Cunard St, Laval, PQ H7S 2G5, Canada

[2] Boehringer Ingelheim Pharmaceut Inc, 900 Ridgebury Rd, Ridgefield, CT 06877 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2016年 / 7卷 / 05期

关键词：

HCMV; cell-to-cell spread; replication inhibitors; antiviral agents; PREVENTION; INFECTION; FUSION;

D O I：

10.1021/acsmedchemlett.6b00064

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A high-throughput screen based on a viral replication assay was used to identify inhibitors of the human cytomegalovirus. Using this approach, hit compound 1 was identified as a 4 mu M inhibitor of HCMV that was specific and selective over other herpes viruses. Time of addition studies indicated compound 1 exerted its antiviral effect early in the viral life cycle. Mechanism of action studies also revealed that this series inhibited infection of MRC-5 and ARPE19 cells by free virus and via direct cell-to-cell spread from infected to uninfected cells. Preliminary structure activity relationships demonstrated that the potency of compound 1 could be improved to a low nanomolar level, but metabolic stability was a key optimization parameter for this series. A strategy focused on minimizing metabolic hydrolysis of the N1-amide led to an alternative scaffold in this series with improved metabolic stability and good pharmacokinetic parameters in rat.

引用

页码：525 / 530

页数：6

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