SAR studies of 4-acyl-1,6-dialkylpiperazin-2-one arenavirus cell entry inhibitors

Michael B. Plewe, Landon R. Whitby, Shibani Naik, Eric R. Brown, Nadezda V. Sokolova, Vidyasagar Reddy Gantla, Joanne York, Jack H. Nunberg, Lihong Zhang, Birte Kalveram, Alexander N. Freiberg, Dale L. Boger, Greg Henkel, Ken McCormack

Research output: Contribution to journalArticle

Abstract

Old World (Africa) and New World (South America) arenaviruses are associated with human hemorrhagic fevers. Efforts to develop small molecule therapeutics have yielded several chemical series including the 4-acyl-1,6-dialkylpiperazin-2-ones. Herein, we describe an extensive exploration of this chemotype. In initial Phase I studies, R1 and R4 scanning libraries were assayed to identify potent substituents against Old World (Lassa) virus. In subsequent Phase II studies, R6 substituents and iterative R1, R4 and R6 substituent combinations were evaluated to obtain compounds with improved Lassa and New World (Machupo, Junin, and Tacaribe) arenavirus inhibitory activity, in vitro human liver microsome metabolic stability and aqueous solubility.

Original languageEnglish (US)
Article number126620
JournalBioorganic and Medicinal Chemistry Letters
DOIs
StateAccepted/In press - Jan 1 2019

Keywords

  • Arenavirus
  • Entry inhibitor
  • Junin
  • Lassa
  • Machupo
  • Piperazinone

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Plewe, M. B., Whitby, L. R., Naik, S., Brown, E. R., Sokolova, N. V., Gantla, V. R., York, J., Nunberg, J. H., Zhang, L., Kalveram, B., Freiberg, A. N., Boger, D. L., Henkel, G., & McCormack, K. (Accepted/In press). SAR studies of 4-acyl-1,6-dialkylpiperazin-2-one arenavirus cell entry inhibitors. Bioorganic and Medicinal Chemistry Letters, [126620]. https://doi.org/10.1016/j.bmcl.2019.08.024