In Vitro Pharmacokinetic Optimizations of AM2-S31N Channel Blockers Led to the Discovery of Slow-Binding Inhibitors with Potent Antiviral Activity against Drug-Resistant Influenza A Viruses

• Published in: Journal of medicinal chemistry Vol. 61; no. 3; pp. 1074 - 1085
• Main Authors: Wang, Yuanxiang, Hu, Yanmei, Xu, Shuting, Zhang, Yongtao, Musharrafieh, Rami, Hau, Raymond Kin, Ma, Chunlong, Wang, Jun
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.02.2018; Amer Chemical Soc
• Subjects: Animals; Antiviral Agents - chemistry; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; Chemistry, Medicinal; Drug Discovery; Drug Resistance, Viral - drug effects; Influenza A virus - drug effects; Influenza A virus - metabolism; Life Sciences & Biomedicine; Mice; Models, Molecular; Pharmacology & Pharmacy; Protein Conformation; Science & Technology; Tissue Distribution; Viral Matrix Proteins - antagonists & inhibitors; Viral Matrix Proteins - chemistry; M2 PROTON CHANNEL; COMBINATIONS; S31N MUTANT; EPIDEMIOLOGY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b01536

Influenza viruses are respiratory pathogens that are responsible for both seasonal influenza epidemics and occasional influenza pandemics. The narrow therapeutic window of oseltamivir, coupled with the emergence of drug resistance, calls for the next-generation of antivirals. With our continuous interest in developing AM2-S31N inhibitors as oral influenza antivirals, we report here the progress of optimizing the in vitro pharmacokinetic (PK) properties of AM2-S31N inhibitors. Several AM2-S31N inhibitors, including compound 10b, were discovered to have potent channel blockage, single to submicromolar antiviral activity, and favorable in vitro PK properties. The antiviral efficacy of compound 10b was also synergistic with oseltamivir carboxylate. Interestingly, binding kinetic studies (K d, K on, and K off) revealed several AM2-S31N inhibitors that have similar K d values but significantly different K on and K off values. Overall, this study identified a potent lead compound (10b) with improved in vitro PK properties that is suitable for the in vivo mouse model studies.