1259012-01-5Relevant academic research and scientific papers
Discovery of Novel, Orally Bioavailable β-Amino Acid Azaindole Inhibitors of Influenza PB2
Farmer, Luc J.,Clark, Michael P.,Boyd, Michael J.,Perola, Emanuele,Jones, Steven M.,Tsai, Alice,Jacobs, Marc D.,Bandarage, Upul K.,Ledeboer, Mark W.,Wang, Tiansheng,Deng, Hongbo,Ledford, Brian,Gu, Wenxin,Duffy, John P.,Bethiel, Randy S.,Shannon, Dean,Byrn, Randal A.,Leeman, Joshua R.,Rijnbrand, Rene,Bennett, Hamilton B.,O’Brien, Colleen,Memmott, Christine,Nti-Addae, Kwame,Bennani, Youssef L.,Charifson, Paul S.
, p. 256 - 260 (2017/03/08)
In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic β-amino acid inhibitors, highlighted by compound 4. Compound 4 showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound 4 offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza.
Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2
Clark, Michael P.,Ledeboer, Mark W.,Davies, Ioana,Byrn, Randal A.,Jones, Steven M.,Perola, Emanuele,Tsai, Alice,Jacobs, Marc,Nti-Addae, Kwame,Bandarage, Upul K.,Boyd, Michael J.,Bethiel, Randy S.,Court, John J.,Deng, Hongbo,Duffy, John P.,Dorsch, Warren A.,Farmer, Luc J.,Gao, Huai,Gu, Wenxin,Jackson, Katrina,Jacobs, Dylan H.,Kennedy, Joseph M.,Ledford, Brian,Liang, Jianglin,Maltais, Fran?ois,Murcko, Mark,Wang, Tiansheng,Wannamaker, M. Woods,Bennett, Hamilton B.,Leeman, Joshua R.,McNeil, Colleen,Taylor, William P.,Memmott, Christine,Jiang, Min,Rijnbrand, Rene,Bral, Christopher,Germann, Ursula,Nezami, Azin,Zhang, Yuegang,Salituro, Francesco G.,Bennani, Youssef L.,Charifson, Paul S.
, p. 6668 - 6678 (2014/10/15)
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.
INHIBITORS OF INFLUENZA VIRUSES REPLICATION
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Page/Page column 66, (2013/03/26)
Methods of inhibiting the replication of influenza viruses in a biological sample or patient, of reducing the amount of influenza viruses in a biological sample or patient, and of treating influenza in a patient, comprises administering to said biological sample or patient an effective amount of a compound represented by Structural Formula (I): or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (I) are as described herein. A compound is represented by Structural Formula (I) or a pharmaceutically acceptable salt thereof, wherein the values of Structural Formula (I) are as described herein. A pharmaceutical composition comprises an effective amount of such a compound or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
