Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (part I)

Bioorg Med Chem Lett. 2013 Jun 1;23(11):3416-20. doi: 10.1016/j.bmcl.2013.03.080. Epub 2013 Mar 29.

Abstract

A series of structurally novel aryl ureas was derived from optimization of the HTS lead as selective histamine H3 receptor (H3R) antagonists. The SAR was explored and the data obtained set up the starting point and foundation for further optimization. The most potent tool compounds, as exemplified by compounds 2l, 5b, 5d, and 5e, displayed antagonism potencies in the subnanomolar range in in vitro human-H3R FLIPR assays and rhesus monkey H3R binding assays.

MeSH terms

  • Amides / chemistry*
  • Amides / metabolism
  • Amides / therapeutic use
  • Animals
  • Drug Evaluation, Preclinical
  • HEK293 Cells
  • Histamine H3 Antagonists / chemistry*
  • Histamine H3 Antagonists / metabolism
  • Histamine H3 Antagonists / therapeutic use
  • Humans
  • Macaca mulatta
  • Obesity / drug therapy
  • Protein Binding
  • Rats
  • Receptors, Histamine H3 / chemistry*
  • Receptors, Histamine H3 / genetics
  • Receptors, Histamine H3 / metabolism
  • Structure-Activity Relationship
  • Urea / chemistry*
  • Urea / metabolism
  • Urea / therapeutic use

Substances

  • Amides
  • Histamine H3 Antagonists
  • Receptors, Histamine H3
  • Urea