Discovery of Potent, Orally Bioavailable Inhibitors of Human Cytomegalovirus.
Basic Information
ID: ALA3808290
Journal: ACS Med Chem Lett
Title: Discovery of Potent, Orally Bioavailable Inhibitors of Human Cytomegalovirus.
Authors: Fader L, Brault M, Desjardins J, Dansereau N, Lamorte L, Tremblay S, Bilodeau F, Bordeleau J, Duplessis M, Gorys V, Gillard J, Gleason JL, James C, Joly MA, Kuhn C, Llinas-Brunet M, Luo L, Morency L, Morin S, Parisien M, Poirier M, Thibeault C, Trinh T, Sturino C, Srivastava S, Yoakim C, Franti M.
Abstract: 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.
CiteXplore: 27190604
DOI: 10.1021/acsmedchemlett.6b00064
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