Synthesis and structure-activity relationships of a series of 4-methoxy-3-(piperidin-4-yl)oxy benzamides as novel inhibitors of the presynaptic choline transporter

Sean R. Bollinger; Darren W. Engers; Elizabeth A. Ennis; Jane Wright; Charles W. Locuson; Craig W. Lindsley; Randy D. Blakely; Corey R. Hopkins

doi:10.1016/j.bmcl.2015.02.058

Synthesis and structure-activity relationships of a series of 4-methoxy-3-(piperidin-4-yl)oxy benzamides as novel inhibitors of the presynaptic choline transporter

Sean R. Bollinger, Darren W. Engers, Elizabeth A. Ennis, Jane Wright, Charles W. Locuson, Craig W. Lindsley, Randy D. Blakely, Corey R. Hopkins

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

3 Scopus citations

Abstract

The synthesis and SAR of 4-methoxy-3-(piperidin-4-yl) benzamides identified after a high-throughput screen of the MLPCN library is reported. SAR was explored around the 3-piperidine substituent as well as the amide functionality of the reported compounds. Starting from the initial lead compounds, 1-7, iterative medicinal chemistry efforts led to the identification of ML352 (10m). ML352 represents a potent and selective inhibitor of CHT based on a drug-like scaffold.

Original language	English (US)
Pages (from-to)	1757-1760
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	25
Issue number	8
DOIs	https://doi.org/10.1016/j.bmcl.2015.02.058
State	Published - Apr 15 2015
Externally published	Yes

Keywords

CHT
Choline transporter
ML352
MLPCN
Structure-activity relationship

ASJC Scopus subject areas

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

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Bollinger, S. R., Engers, D. W., Ennis, E. A., Wright, J., Locuson, C. W., Lindsley, C. W., Blakely, R. D., & Hopkins, C. R. (2015). Synthesis and structure-activity relationships of a series of 4-methoxy-3-(piperidin-4-yl)oxy benzamides as novel inhibitors of the presynaptic choline transporter. Bioorganic and Medicinal Chemistry Letters, 25(8), 1757-1760. https://doi.org/10.1016/j.bmcl.2015.02.058

Synthesis and structure-activity relationships of a series of 4-methoxy-3-(piperidin-4-yl)oxy benzamides as novel inhibitors of the presynaptic choline transporter. / Bollinger, Sean R.; Engers, Darren W.; Ennis, Elizabeth A.; Wright, Jane; Locuson, Charles W.; Lindsley, Craig W.; Blakely, Randy D.; Hopkins, Corey R.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 25, No. 8, 15.04.2015, p. 1757-1760.

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

Bollinger, SR, Engers, DW, Ennis, EA, Wright, J, Locuson, CW, Lindsley, CW, Blakely, RD & Hopkins, CR 2015, 'Synthesis and structure-activity relationships of a series of 4-methoxy-3-(piperidin-4-yl)oxy benzamides as novel inhibitors of the presynaptic choline transporter', Bioorganic and Medicinal Chemistry Letters, vol. 25, no. 8, pp. 1757-1760. https://doi.org/10.1016/j.bmcl.2015.02.058

Bollinger, Sean R. ; Engers, Darren W. ; Ennis, Elizabeth A. ; Wright, Jane ; Locuson, Charles W. ; Lindsley, Craig W. ; Blakely, Randy D. ; Hopkins, Corey R. / Synthesis and structure-activity relationships of a series of 4-methoxy-3-(piperidin-4-yl)oxy benzamides as novel inhibitors of the presynaptic choline transporter. In: Bioorganic and Medicinal Chemistry Letters. 2015 ; Vol. 25, No. 8. pp. 1757-1760.

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abstract = "The synthesis and SAR of 4-methoxy-3-(piperidin-4-yl) benzamides identified after a high-throughput screen of the MLPCN library is reported. SAR was explored around the 3-piperidine substituent as well as the amide functionality of the reported compounds. Starting from the initial lead compounds, 1-7, iterative medicinal chemistry efforts led to the identification of ML352 (10m). ML352 represents a potent and selective inhibitor of CHT based on a drug-like scaffold.",

keywords = "CHT, Choline transporter, ML352, MLPCN, Structure-activity relationship",

author = "Bollinger, {Sean R.} and Engers, {Darren W.} and Ennis, {Elizabeth A.} and Jane Wright and Locuson, {Charles W.} and Lindsley, {Craig W.} and Blakely, {Randy D.} and Hopkins, {Corey R.}",

note = "Funding Information: The authors would like to thank Mr. Ryan Morrison and Frank Byers for technical assistance with the PK experiments. Vanderbilt is a member of the MLPCN and houses the Vanderbilt Specialized Chemistry Center for Accelerated Probe Development. This work was generously supported by the NIH/MLPCN Grant U54 MH084659 (C.W.L.). In addition, this work was supported by CTSA award UL1TR000445 from the National Center for Advancing Translational Sciences (EAE), and NIH Awards GM07628 (EAE), MH073159 (RDB), and a Zenith Award from the Alzheimer{\textquoteright}s Foundation (RDB).",

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AU - Wright, Jane

AU - Locuson, Charles W.

AU - Lindsley, Craig W.

AU - Blakely, Randy D.

AU - Hopkins, Corey R.

N1 - Funding Information: The authors would like to thank Mr. Ryan Morrison and Frank Byers for technical assistance with the PK experiments. Vanderbilt is a member of the MLPCN and houses the Vanderbilt Specialized Chemistry Center for Accelerated Probe Development. This work was generously supported by the NIH/MLPCN Grant U54 MH084659 (C.W.L.). In addition, this work was supported by CTSA award UL1TR000445 from the National Center for Advancing Translational Sciences (EAE), and NIH Awards GM07628 (EAE), MH073159 (RDB), and a Zenith Award from the Alzheimer’s Foundation (RDB).

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