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

Optimization and SAR research at the benzoxazole and tetrazole rings of JNJ4796 as new anti-influenza A virus agents, part 2

  • Eur J Med Chem. 2023 Jan 5;245(Pt 1):114906. doi: 10.1016/j.ejmech.2022.114906.
Wenhao Wu 1,  Haiyan Yan 2,  Bin Jiang 1,  Aoyu Wang 1,  Xingqiong Li 2,  Yuehao Zhang 1,  Jizhou Wu 2,  Xijun Zhong 2,  Rongmei Gao 2,  Apeng Wang 2,  Kai Lv 3,  Yuhuan Li 4,  Mingliang Liu 5
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; Department of Pharmaceutical Chemistry, School of Pharmacy, Hebei Medical University, Shijiazhuang, 050017, China. Electronic address: [email protected].
  • 4 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].
  • 5 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: 36395647 DOI: 10.1016/j.ejmech.2022.114906
Abstract

We have already reported the modification on the piperazine and phenyl rings of JNJ4796, a small-molecule fuse inhibitor targeting hemagglutinin (HA). In this study, we described the structure-activity relationship of the benzoxazole and tetrazole rings of JNJ4796. Many derivatives demonstrated good in vitro activity against IAV H1N1and Oseltamivir-resistant IAV H1N1 stains. Although compounds (R)-1e and (R)-1h exhibited excellent in vitro activity, high drug exposure level and low hERG inhibition, they displayed low oral efficacy. Excitedly, (R)-1a, a representative identified in our previous study, was found to show potent in vivo anti-IAV activity with the survival rates of 100%, 100% and 70% at 15, 5 and 1.67 mg/kg, respectively, comparable to JNJ4796. Currently, we are exploring different ways to ease its gastrointestinal response.

Keywords

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

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