1. Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2
- Author
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Marc Jacobs, Christopher Bral, Youssef L. Bennani, Jianglin Liang, John P. Duffy, Tiansheng Wang, Brian Ledford, Michael J. Boyd, Wenxin Gu, Randal Byrn, Min Jiang, Christine Memmott, Azin Nezami, Ioana Davies, Joshua R. Leeman, Yuegang Zhang, Hamilton B. Bennett, Warren Dorsch, Katrina L. Jackson, Upul K. Bandarage, William P. Taylor, Mark W. Ledeboer, Dylan Jacobs, Francesco G. Salituro, Kennedy Joseph M, Huai Gao, Nti-Addae Kwame Wiredu, Michael P. Clark, Francois Maltais, Emanuele Perola, Murcko Mark A, Deng Hongbo, M. Woods Wannamaker, Ursula A. Germann, Alice Tsai, Rene Rijnbrand, Luc J. Farmer, Colleen F. McNeil, Randy S. Bethiel, Paul S. Charifson, John J. Court, and Jones Steven
- Subjects
Male ,Models, Molecular ,Indoles ,Phenotypic screening ,Cell ,Administration, Oral ,Biological Availability ,Biology ,Pharmacology ,medicine.disease_cause ,Virus Replication ,Antiviral Agents ,Madin Darby Canine Kidney Cells ,Structure-Activity Relationship ,Viral Proteins ,Dogs ,Orthomyxoviridae Infections ,Species Specificity ,Drug Discovery ,Pandemic ,Drug Resistance, Viral ,medicine ,BDNA test ,Potency ,Animals ,Polymerase ,Aza Compounds ,Mice, Inbred BALB C ,Molecular Structure ,virus diseases ,Stereoisomerism ,RNA-Dependent RNA Polymerase ,Virology ,Influenza A virus subtype H5N1 ,Rats ,medicine.anatomical_structure ,Viral replication ,Influenza A virus ,biology.protein ,Molecular Medicine - Abstract
In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay (Wagaman, P. C., Leong, M. A., and Simmen, K. A. Development of a novel influenza A antiviral assay. J. Virol. Methods 2002, 105, 105-114) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window.
- Published
- 2014