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

doi:10.1016/j.bmcl.2019.08.024

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

Pathology

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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 language	English (US)
Article number	126620
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	29
Issue number	22
DOIs	https://doi.org/10.1016/j.bmcl.2019.08.024
State	Published - Nov 15 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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10.1016/j.bmcl.2019.08.024

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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. (2019). SAR studies of 4-acyl-1,6-dialkylpiperazin-2-one arenavirus cell entry inhibitors. Bioorganic and Medicinal Chemistry Letters, 29(22), Article 126620. https://doi.org/10.1016/j.bmcl.2019.08.024

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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.",

keywords = "Arenavirus, Entry inhibitor, Junin, Lassa, Machupo, Piperazinone",

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

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doi = "10.1016/j.bmcl.2019.08.024",

language = "English (US)",

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AU - Plewe, Michael B.

AU - Whitby, Landon R.

AU - Naik, Shibani

AU - Brown, Eric R.

AU - Sokolova, Nadezda V.

AU - Gantla, Vidyasagar Reddy

AU - York, Joanne

AU - Nunberg, Jack H.

AU - Zhang, Lihong

AU - Kalveram, Birte

AU - Freiberg, Alexander N.

AU - Boger, Dale L.

AU - Henkel, Greg

AU - McCormack, Ken

PY - 2019/11/15

Y1 - 2019/11/15

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AB - 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.

KW - Arenavirus

KW - Entry inhibitor

KW - Junin

KW - Lassa

KW - Machupo

KW - Piperazinone

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

Abstract

Keywords

ASJC Scopus subject areas

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