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. Epub 2015 Feb 28.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / chemical synthesis
  • Benzamides / chemistry*
  • Benzamides / pharmacokinetics
  • HEK293 Cells
  • Half-Life
  • Humans
  • Membrane Transport Proteins / chemistry*
  • Membrane Transport Proteins / metabolism
  • Piperidines / chemistry
  • Protein Binding
  • Rats
  • Structure-Activity Relationship
  • Symporters / antagonists & inhibitors
  • Symporters / metabolism
  • Tissue Distribution

Substances

  • Benzamides
  • Membrane Transport Proteins
  • Piperidines
  • SLC5A7 protein, human
  • Symporters
  • choline transporter
  • piperidine