Optimization of 4‑Aminopiperidines as Inhibitors of Influenza A Viral Entry That Are Synergistic with Oseltamivir

• Published in: Journal of medicinal chemistry 2020-03, Vol.63 (6), p.3120-3130
• Main Authors: Gaisina, Irina N, Peet, Norton P, Cheng, Han, Li, Ping, Du, Ruikun, Cui, Qinghua, Furlong, Kevin, Manicassamy, Balaji, Caffrey, Michael, Thatcher, Gregory R. J, Rong, Lijun
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - metabolism; Antiviral Agents - pharmacology; Binding Sites; Dogs; Drug Synergism; Hemagglutinins, Viral - chemistry; Hemagglutinins, Viral - metabolism; Humans; Influenza A Virus, H1N1 Subtype - chemistry; Influenza A Virus, H1N1 Subtype - drug effects; Influenza A Virus, H5N1 Subtype - chemistry; Influenza A Virus, H5N1 Subtype - drug effects; Madin Darby Canine Kidney Cells; Mice; Microbial Sensitivity Tests; Microsomes, Liver - metabolism; Molecular Docking Simulation; Molecular Structure; Oseltamivir - pharmacology; Piperidines - chemical synthesis; Piperidines - metabolism; Piperidines - pharmacology; Protein Binding; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; Virus Internalization - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.9b01900

Vaccination is the most prevalent prophylactic means for controlling seasonal influenza infections. However, an effective vaccine usually takes at least 6 months to develop for the circulating strains. Therefore, new therapeutic options are needed for the acute treatment of influenza infections to control this virus and prevent epidemics/pandemics from developing. We have discovered fast-acting, orally bioavailable acylated 4-aminopiperidines with an effective mechanism of action targeting viral hemagglutinin (HA). Our data show that these compounds are potent entry inhibitors of influenza A viruses. We present docking studies that suggest an HA binding site for these inhibitors on H5N1. Compound 16 displayed a significant decrease of viral titer when evaluated in the infectious assays with influenza virus H1N1 (A/Puerto Rico/8/1934) or H5N1 (A/Vietnam/1203/2004) strains and the oseltamivir-resistant strain with the most common H274Y mutation. In addition, compound 16 showed significant synergistic activity with oseltamivir in vitro.