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

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

  • Eur J Med Chem. 2021 Oct 15:222:113591. doi: 10.1016/j.ejmech.2021.113591.
Aoyu Wang 1,  Yuhuan Li 2,  Kai Lv 3,  Rongmei Gao 2,  Apeng Wang 2,  Haiyan Yan 2,  Xiaoyu Qin 2,  Shijie Xu 2,  Chao Ma 2,  Jiandong Jiang 2,  Zengquan Wei 4,  Kai Zhang 5,  Mingliang Liu 6
Affiliations

Affiliations

  • 1 CAMS Key Laboratory of Antiviral Drug Research, Beijing Key Laboratory of Antimicrobial Agents, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Department of Pharmaceutical Chemistry, School of Pharmacy, Hebei Medical University, Shijiazhuang, 050017, China.
  • 2 CAMS Key Laboratory of Antiviral Drug Research, Beijing Key Laboratory of Antimicrobial Agents, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
  • 3 CAMS Key Laboratory of Antiviral Drug Research, Beijing Key Laboratory of Antimicrobial Agents, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
  • 4 Chemical Medicine Department, R&D Center, Tasly Pharmaceutical Group Co. Ltd., Tianjin, 300410, China.
  • 5 Department of Pharmaceutical Chemistry, School of Pharmacy, Hebei Medical University, Shijiazhuang, 050017, China. Electronic address: [email protected].
  • 6 CAMS Key Laboratory of Antiviral Drug Research, Beijing Key Laboratory of Antimicrobial Agents, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: [email protected].
PMID: 34126455 DOI: 10.1016/j.ejmech.2021.113591
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.

Keywords

Hemagglutinin inhibitors; Influenza A virus; JNJ4796; Structure-activity relationship.

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