tetano
Editor, Senior Moderator
J Med Chem. 2014 Jul 14. [Epub ahead of print]
The Discovery of a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor (VX-787) of Influenza PB2.
Clark MP, Ledeboer MW, Davies I, Byrn R, Jones S, Perola E, Tsai A, Jacobs M, Nti-Addae K, Bandarage U, Boyd M, Bethiel R, Court J, Deng H, Duffy JP, Dorsch W, Farmer L, Gao H, Gu W, Jackson K, Jacobs D, Kennedy J, Ledford B, Liang J, Maltais F, Murcko M, Wang T, Wannamaker W, Bennett HB, Leeman J, McNeil C, Taylor W, Memmott C, Jiang M, Rijnbrand R, Bral C, Germann UA, Nezami A, Zhang Y, Salituro F, Bennani YL, Charifson PS.
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 assay1 in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogs, highlighted by VX-787 (2). VX-787 shows strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows a efficacy profile in a mouse influenza model even when treatment was administered 48h post infection. VX-787 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.
PMID:
25019388
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/25019388
The Discovery of a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor (VX-787) of Influenza PB2.
Clark MP, Ledeboer MW, Davies I, Byrn R, Jones S, Perola E, Tsai A, Jacobs M, Nti-Addae K, Bandarage U, Boyd M, Bethiel R, Court J, Deng H, Duffy JP, Dorsch W, Farmer L, Gao H, Gu W, Jackson K, Jacobs D, Kennedy J, Ledford B, Liang J, Maltais F, Murcko M, Wang T, Wannamaker W, Bennett HB, Leeman J, McNeil C, Taylor W, Memmott C, Jiang M, Rijnbrand R, Bral C, Germann UA, Nezami A, Zhang Y, Salituro F, Bennani YL, Charifson PS.
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 assay1 in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogs, highlighted by VX-787 (2). VX-787 shows strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows a efficacy profile in a mouse influenza model even when treatment was administered 48h post infection. VX-787 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.
PMID:
25019388
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/25019388