2. Academic Validation
  3. Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2

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

Affiliation

  • 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.

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