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Bioorg Med Chem Lett. 2015 Apr 15;25(8):1757-1760. doi: 10.1016/j.bmcl.2015.02.058. Epub 2015 Feb 28.

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.

Author information

1
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
2
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
3
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.
4
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
5
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA. Electronic address: corey.r.hopkins@vanderbilt.edu.

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

PMID:
25801932
PMCID:
PMC4385452
DOI:
10.1016/j.bmcl.2015.02.058
[Indexed for MEDLINE]
Free PMC Article

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