title: Discovery of Potent, Orally Bioavailable Inhibitors of Human Cytomegalovirus.
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.
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Lee
authors.initials: L
authors.lastname: Fader
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Martine
authors.initials: M
authors.lastname: Brault
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Desjardins
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dansereau
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Louie
authors.initials: L
authors.lastname: Lamorte
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Sonia
authors.initials: S
authors.lastname: Tremblay
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Bilodeau
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Josée
authors.initials: J
authors.lastname: Bordeleau
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Duplessis
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Vida
authors.initials: V
authors.lastname: Gorys
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Gillard
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: James L
authors.initials: JL
authors.lastname: Gleason
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Clint
authors.initials: C
authors.lastname: James
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Joly
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Kuhn
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Montse
authors.initials: M
authors.lastname: Llinas-Brunet
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Laibin
authors.initials: L
authors.lastname: Luo
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Louis
authors.initials: L
authors.lastname: Morency
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Morin
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Parisien
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Maude
authors.initials: M
authors.lastname: Poirier
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Carl
authors.initials: C
authors.lastname: Thibeault
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Thao
authors.initials: T
authors.lastname: Trinh
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Claudio
authors.initials: C
authors.lastname: Sturino
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Christiane
authors.initials: C
authors.lastname: Yoakim
authors.affiliation: Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Franti
keywords: HCMV; antiviral agents; cell-to-cell spread; replication inhibitors