Optimization and SAR research at the piperazine and phenyl rings of JNJ4796 as new anti-influenza A virus agents, part 1.
Wang A, Li Y, Lv K, Gao R, Wang A, Yan H, Qin X, Xu S, Ma C, Jiang J, Wei Z, Zhang K, Liu M.
JNJ4796, a small molecule fuse inhibitor targeting the conserved stem region of hemagglutinin, effectively neutralized a broad spectrum of group 1 influenza A virus (IAV), and protected mice against lethal and sublethal influenza challenge after oral administration. In this study, we reported the modification and structure-activity relationship (SAR) of C (piperazine ring) and E (phenyl ring) rings of JNJ4796. Compound (R)-2c was identified to show excellent in vitro activity against IAV H1N1 and Oseltamivir-resistant IAV H1N1 stains (IC<sub>50</sub>: 0.03-0.06 μM), low cytotoxicity (CC<sub>50</sub> > 200 μM), accepted oral PK profiles and low inhibition rate of hERG (13.2%, at 10 μM). Evaluation for the in vivo anti-IAV efficacy of (R)-2c will begin soon.