期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 3, 页码 1207-1216出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01910
关键词
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资金
- NIH [AI119187, GM056423, AI74571]
- PhRMA foundation research starter grant in pharmacology and toxicology
With the emergence of highly pathogenic avian influenza (HPAI) H7N9 and HSN1 strains, there is a pressing need to develop direct-acting antivirals (DAAs) to combat such deadly viruses. The M2-S31N proton channel of the influenza A virus (A/M2) is one of the validated and most conserved proteins encoded by the current circulating influenza A viruses; thus, it represents a high-profile drug target for therapeutic intervention. We recently discovered a series of S31N inhibitors with the general structure of adamantyl-1-NH2+CH2-aryl, but they generally had poor physical properties and some showed toxicity in vitro. In this study, we sought to optimize both the adamantyl as well as the aryl/heteroaryl group. Several compounds from this study exhibited submicromolar EC50 values against S31N-containing A/WSN/33 influenza viruses in antiviral plaque reduction assays with a selectivity index greater than 100, indicating that these compounds are promising candidates for in-depth preclinical pharmacology.
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