Optimization and SAR research at the piperazine and phenyl rings of JNJ4796 as new anti-influenza A virus agents, part 1.

ABSTRACT

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 (IC50 0.03-0.06 µM), low cytotoxicity (CC50 > 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.