Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2.
Michael P Clark, Mark W Ledeboer, Ioana Davies, Randal A Byrn, Steven M Jones, Emanuele Perola, Alice Tsai, Marc Jacobs, Kwame Nti-Addae, Upul K Bandarage, Michael J Boyd, Randy S Bethiel, John J Court, Hongbo Deng, John P Duffy, Warren A Dorsch, Luc J Farmer, Huai Gao, Wenxin Gu, Katrina Jackson, Dylan H Jacobs, Joseph M Kennedy, Brian Ledford, Jianglin Liang, François Maltais, Mark Murcko, Tiansheng Wang, M Woods Wannamaker, Hamilton B Bennett, Joshua R Leeman, Colleen McNeil, William P Taylor, Christine Memmott, Min Jiang, Rene Rijnbrand, Christopher Bral, Ursula Germann, Azin Nezami, Yuegang Zhang, Francesco G Salituro, Youssef L Bennani, Paul S Charifson
Author Information
Michael P Clark: Vertex Pharmaceuticals Inc. , 50 Northern Ave, Boston, Massachusetts 02210, United States.
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.
