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

  • Bioorg Med Chem Lett. 2015 Apr 15;25(8):1757-1760. doi: 10.1016/j.bmcl.2015.02.058.
Sean R Bollinger  1 ,  Darren W Engers  1 ,  Elizabeth A Ennis  2 ,  Jane Wright  2 ,  Charles W Locuson  1 ,  Craig W Lindsley  3 ,  Randy D Blakely  4 ,  Corey R Hopkins  5
Affiliations
  • 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: [email protected].
PMID: 25801932 DOI: 10.1016/j.bmcl.2015.02.058
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.