5BUH

Influenza PB2 bound to a hydroxymethyl azaindole inhibitor

5BUH の概要

• エントリーDOI: 10.2210/pdb5buh/pdb
• 分子名称: Polymerase basic protein 2, N-[(1R,3S)-3-({5-fluoro-2-[5-fluoro-2-(hydroxymethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl}amino)cyclohexyl]pyrrolidine-1-carboxamide (3 entities in total)
• 機能のキーワード: small molecule inhibitor, polymerase, influenza, immune system
• 由来する生物種: Influenza A virus
• 細胞内の位置: Virion : Q30NP1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19645.83

構造登録者

Jacobs, M.D. (登録日: 2015-06-03, 公開日: 2016-06-08, 最終更新日: 2024-03-06)

主引用文献

Bandarage, U.K.,Clark, M.P.,Perola, E.,Gao, H.,Jacobs, M.D.,Tsai, A.,Gillespie, J.,Kennedy, J.M.,Maltais, F.,Ledeboer, M.W.,Davies, I.,Gu, W.,Byrn, R.A.,Nti Addae, K.,Bennett, H.,Leeman, J.R.,Jones, S.M.,O'Brien, C.,Memmott, C.,Bennani, Y.,Charifson, P.S.
Novel 2-Substituted 7-Azaindole and 7-Azaindazole Analogues as Potential Antiviral Agents for the Treatment of Influenza.
ACS Med Chem Lett, 8:261-265, 2017

PubMed Abstract: JNJ-63623872 () 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 () 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.

PubMed: 28197323
DOI: 10.1021/acsmedchemlett.6b00487

実験手法

X-RAY DIFFRACTION (2.55 Å)