Identification and profiling of 3,5-dimethyl-isoxazole-4-carboxylic acid [2-methyl-4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)phenyl] amide as histamine H(3) receptor antagonist for the treatment of depression

Bioorg Med Chem Lett. 2013 Dec 1;23(23):6269-73. doi: 10.1016/j.bmcl.2013.09.081. Epub 2013 Oct 3.

Abstract

Lead optimization guided by histamine H3 receptor (H3R) affinity and calculated physico-chemical properties enabled simultaneous improvement in potency and PK properties leading to the identification of a potent, selective, devoid of hERG issues, orally bioavailable, and CNS penetrable H3R antagonist/inverse agonist 3h. The compound was active in forced-swimming tests suggesting its potential therapeutic utility as an anti-depressive agent. This Letter further includes its cardiovascular and neuropsychological/behavioral safety assessments.

Keywords: Anxiety; Depression; Experimental models of anxiety and depression; Forced swimming test; Histamine H(3) receptor antagonist/inverse agonist.

MeSH terms

  • Amides / chemistry*
  • Amides / pharmacokinetics
  • Amides / pharmacology
  • Animals
  • Antidepressive Agents / chemistry*
  • Antidepressive Agents / pharmacokinetics
  • Antidepressive Agents / pharmacology
  • CHO Cells
  • Cricetulus
  • Histamine Antagonists / chemistry*
  • Histamine Antagonists / pharmacokinetics
  • Histamine Antagonists / pharmacology
  • Humans
  • Kinetics
  • Male
  • Mice
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacokinetics
  • Pyrrolidines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Histamine H3 / chemistry
  • Receptors, Histamine H3 / metabolism

Substances

  • Amides
  • Antidepressive Agents
  • Histamine Antagonists
  • Pyrrolidines
  • Receptors, Histamine H3