| Literature DB >> 28197322 |
Luc J Farmer1, Michael P Clark1, Michael J Boyd1, Emanuele Perola1, Steven M Jones1, Alice Tsai1, Marc D Jacobs1, Upul K Bandarage1, Mark W Ledeboer1, Tiansheng Wang1, Hongbo Deng1, Brian Ledford1, Wenxin Gu1, John P Duffy1, Randy S Bethiel1, Dean Shannon1, Randal A Byrn1, Joshua R Leeman1, Rene Rijnbrand1, Hamilton B Bennett1, Colleen O'Brien1, Christine Memmott1, Kwame Nti-Addae1, Youssef L Bennani1, Paul S Charifson1.
Abstract
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.Entities:
Keywords: PB2 inhibitor; azaindole; influenza
Year: 2017 PMID： 28197322 PMCID： PMC5304291 DOI： 10.1021/acsmedchemlett.6b00486
Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345