Benzimidazole- and indole-substituted 1,3'-bipyrrolidine benzamides as histamine H3 receptor antagonists

Bioorg Med Chem Lett. 2010 Feb 1;20(3):1237-40. doi: 10.1016/j.bmcl.2009.11.122. Epub 2009 Dec 4.

Abstract

Using a focused screen of biogenic amine compounds we identified a novel series of H(3)R antagonists. A preliminary SAR study led to reduction of MW while increasing binding affinity and potency. Optimization of the physical properties of the series led to (S)-6n, with improved brain to plasma exposure and efficacy in both water intake and novel object recognition models.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Benzamides / blood
  • Benzamides / chemistry*
  • Benzamides / metabolism
  • Benzimidazoles / blood
  • Benzimidazoles / chemistry*
  • Benzimidazoles / metabolism
  • Caco-2 Cells
  • Cell Line
  • Histamine H3 Antagonists / blood
  • Histamine H3 Antagonists / chemistry*
  • Histamine H3 Antagonists / metabolism
  • Humans
  • Indoles / blood
  • Indoles / chemistry
  • Indoles / metabolism
  • Protein Binding
  • Pyrrolidines / blood
  • Pyrrolidines / chemistry*
  • Pyrrolidines / metabolism
  • Rats
  • Receptors, Histamine H3* / blood
  • Receptors, Histamine H3* / metabolism

Substances

  • Benzamides
  • Benzimidazoles
  • Histamine H3 Antagonists
  • Indoles
  • Pyrrolidines
  • Receptors, Histamine H3
  • benzimidazole