Discovery of Potent, Orally Bioavailable Inhibitors of Human Cytomegalovirus
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- 作者：Lee Fader ; Martine Brault ; Jessica Desjardins ; Nathalie Dansereau ; Louie Lamorte ; Sonia Tremblay ; François Bilodeau ; Josée Bordeleau ; Martin Duplessis ; Vida Gorys ; James Gillard ; James L. Gleason ; Clint James ; Marc-André Joly ; Cyrille Kuhn ; Montse Llinas-Brunet ; Laibin Luo ; Louis Morency ; Sébastien Morin ; Mathieu Parisien ; Maude Poirier ; Carl Thibeault ; Thao Trinh ; Claudio Sturino ; Sanjay Srivastava ; Christiane Yoakim ; Michael Franti
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：May 12, 2016
- 年：2016
- 卷：7
- 期：5
- 页码：525-530
- 全文大小：335K
- 年卷期：0
- ISSN：1948-5875
文摘
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 μM 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.