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

Yuanxiang Wang, Yanmei Hu, Shuting Xu, Yongtao Zhang, Rami Musharrafieh, Raymond Kin Hau, Chunlong Ma, Jun Wang

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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 (Kd, Kon, and Koff) revealed several AM2-S31N inhibitors that have similar Kd values but significantly different Kon and Koff 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.

Original languageEnglish (US)
Pages (from-to)1074-1085
Number of pages12
JournalJournal of Medicinal Chemistry
Volume61
Issue number3
DOIs
StatePublished - Feb 8 2018

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Influenza A virus
Antiviral Agents
Pharmacokinetics
Human Influenza
Pharmaceutical Preparations
Oseltamivir
Pandemics
Orthomyxoviridae
Drug Resistance
In Vitro Techniques
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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. / Wang, Yuanxiang; Hu, Yanmei; Xu, Shuting; Zhang, Yongtao; Musharrafieh, Rami; Hau, Raymond Kin; Ma, Chunlong; Wang, Jun.

In: Journal of Medicinal Chemistry, Vol. 61, No. 3, 08.02.2018, p. 1074-1085.

Research output: Contribution to journalArticle

Wang, Yuanxiang ; Hu, Yanmei ; Xu, Shuting ; Zhang, Yongtao ; Musharrafieh, Rami ; Hau, Raymond Kin ; Ma, Chunlong ; Wang, Jun. / 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. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 3. pp. 1074-1085.
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AU - Zhang, Yongtao

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