Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2

  • J Med Chem. 2014 Aug 14;57(15):6668-78. doi: 10.1021/jm5007275.
Michael P Clark  1 ,  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
Affiliations
  • 1. Vertex Pharmaceuticals Inc. , 50 Northern Ave, Boston, Massachusetts 02210, United States.
PMID: 25019388 DOI: 10.1021/jm5007275
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.