1383446-78-3Relevant articles and documents
Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza
Bandarage, Upul K.,Clark, Michael P.,Perola, Emanuele,Gao, Huai,Jacobs, Marc D.,Tsai, Alice,Gillespie, Jeffery,Kennedy, Joseph M.,Maltais, Fran?ois,Ledeboer, Mark W.,Davies, Ioana,Gu, Wenxin,Byrn, Randal A.,Nti Addae, Kwame,Bennett, Hamilton,Leeman, Joshua R.,Jones, Steven M.,O’Brien, Colleen,Memmott, Christine,Bennani, Youssef,Charifson, Paul S.
supporting information, p. 261 - 265 (2017/03/08)
JNJ-63623872 (2) is a first-in-class, orally bioavailable compound that offers significant potential for the treatment of pandemic and seasonal influenza. Early lead optimization efforts in our 7-azaindole series focused on 1,3-diaminocyclohexyl amide and urea substitutions on the pyrimidine-7-azaindole motif. In this work, we explored two strategies to eliminate observed aldehyde oxidase (AO)-mediated metabolism at the 2-position of these 7-azaindole analogues. Substitution at the 2-position of the azaindole ring generated somewhat less potent analogues, but reduced AO-mediated metabolism. Incorporation of a ring nitrogen generated 7-azaindazole analogues that were equipotent to the parent 2-H-7-azaindole, but surprisingly, did not appear to improve AO-mediated metabolism. Overall, we identified multiple 2-substituted 7-azaindole analogues with enhanced AO stability and we present data for one such compound (12) that demonstrate a favorable oral pharmacokinetic profile in rodents. These analogues have the potential to be further developed as anti-influenza agents for the treatment of influenza.
