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

Montana Biotechnology Center

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

7 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
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

Funding

We gratefully acknowledge the financial support of the National Institutes of Health ( R43AI112097 to K.M and M.B.P.; R44AI112097 to G.H.; CA042056 to D.L.B.; AI074818 and AI065357 to J.H.N) and the generous gifts of arenavirus glycoprotein plasmid constructs and pseudotyped vectors from Juan Carlos de la Torre and Brian Hjelle. The replicative Tacaribe virus TRVL-11573 and monoclonal anti-JUNV, clone MA03-BE06 were obtained from BEI Resources, NIAID, NIH. We gratefully acknowledge the financial support of the National Institutes of Health (R43AI112097 to K.M and M.B.P.; R44AI112097 to G.H.; CA042056 to D.L.B.; AI074818 and AI065357 to J.H.N) and the generous gifts of arenavirus glycoprotein plasmid constructs and pseudotyped vectors from Juan Carlos de la Torre and Brian Hjelle. The replicative Tacaribe virus TRVL-11573 and monoclonal anti-JUNV, clone MA03-BE06 were obtained from BEI Resources, NIAID, NIH.

Funder number
AI074818, MA03-BE06, AI065357, TRVL-11573
R01CA042056
R43AI112097

Keywords

Arenavirus
Entry inhibitor
Junin
Lassa
Machupo
Piperazinone

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10.1016/j.bmcl.2019.08.024

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. (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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title = "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.",

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",

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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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M3 - Article

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JF - Bioorganic and Medicinal Chemistry Letters

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M1 - 126620

ER -

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

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Keywords

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