Discovery of Potent, Orally Bioavailable Inhibitors of Human Cytomegalovirus.
| Title: | Discovery of Potent, Orally Bioavailable Inhibitors of Human Cytomegalovirus. |
|---|---|
| Authors: | Fader L; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Brault M; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Desjardins J; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Dansereau N; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Lamorte L; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Tremblay S; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Bilodeau F; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Bordeleau J; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Duplessis M; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Gorys V; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Gillard J; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Gleason JL; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; James C; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Joly MA; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Kuhn C; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Llinas-Brunet M; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Luo L; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Morency L; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Morin S; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Parisien M; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Poirier M; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Thibeault C; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Trinh T; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Sturino C; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Srivastava S; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Yoakim C; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada.; Franti M; Research and Development, Boehringer Ingelheim (Canada) Ltd. , 2100 Cunard Street, Laval, Québec H7S 2G5, Canada. |
| Source: | ACS medicinal chemistry letters [ACS Med Chem Lett] 2016 Mar 01; Vol. 7 (5), pp. 525-30. Date of Electronic Publication: 2016 Mar 01 (Print Publication: 2016). |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 101521073 Publication Model: eCollection Cited Medium: Print ISSN: 1948-5875 (Print) Linking ISSN: 19485875 NLM ISO Abbreviation: ACS Med Chem Lett Subsets: PubMed not MEDLINE |
| Imprint Name(s): | Original Publication: Washington, D.C. : American Chemical Society |
| 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. |
| References: | J Virol. 2004 Feb;78(3):1289-300. (PMID: 14722284); J Virol Methods. 2014 Jan;195:67-71. (PMID: 24100066); J Virol. 2005 Jun;79(12):7827-37. (PMID: 15919936); Virology. 2013 Sep;444(1-2):140-7. (PMID: 23849792); Bioorg Med Chem Lett. 2003 Sep 1;13(17):2929-32. (PMID: 14611860); Vaccine. 2014 May 7;32(22):2525-33. (PMID: 24681264); Hum Exp Toxicol. 1991 Jul;10(4):261-73. (PMID: 1679649); J Pathol. 2015 Jan;235(2):288-97. (PMID: 25205255); Cell Mol Life Sci. 2008 Jun;65(11):1653-68. (PMID: 18351291); Chem Rev. 2011 Apr 13;111(4):2507-36. (PMID: 21265518) |
| Contributed Indexing: | Keywords: HCMV; antiviral agents; cell-to-cell spread; replication inhibitors |
| Entry Date(s): | Date Created: 20160519 Date Completed: 20160518 Latest Revision: 20200930 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC4867477 |
| DOI: | 10.1021/acsmedchemlett.6b00064 |
| PMID: | 27190604 |
| Database: | MEDLINE |
Journal Article