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

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.

SUBMITTER: Plewe MB

PROVIDER: S-EPMC6803051 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Plewe Michael B MB Whitby Landon R LR Naik Shibani S Brown Eric R ER Sokolova Nadezda V NV Gantla Vidyasagar Reddy VR York Joanne J Nunberg Jack H JH Zhang Lihong L Kalveram Birte B Freiberg Alexander N AN Boger Dale L DL Henkel Greg G McCormack Ken K

Bioorganic & medicinal chemistry letters 20190824 22

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, R<sup>1</sup> and R<sup>4</sup> scanning libraries were assayed to identify potent substituents against Old World (Lassa) virus. In subsequent Phase II studies, R<sup ...[more]

PMID: 31537423

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