4,5-dihydropyridazin-3-one derivatives as histamine H₃ receptor inverse agonists

Bioorg Med Chem Lett. 2012 Jan 1;22(1):194-8. doi: 10.1016/j.bmcl.2011.11.037. Epub 2011 Nov 16.

Abstract

H(3)R structure-activity relationships for a new class of 4,5-dihydropyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modification of the 4,5-dihydropyridazinone moiety to block in vivo metabolism identified 4,4-dimethyl-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4,5-dihydro-2H-pyridazin-3-one 22 as a lead candidate demonstrating potent in vivo functional H(3)R antagonism in the rat dipsogenia model and robust wake promoting activity in the rat EEG/EMG model.

MeSH terms

  • Animals
  • Area Under Curve
  • Dose-Response Relationship, Drug
  • Drug Design
  • Electroencephalography / methods
  • Electromyography / methods
  • Histamine Agonists / chemical synthesis*
  • Histamine Agonists / pharmacology
  • Kinetics
  • Models, Chemical
  • Pyridazines / chemical synthesis
  • Pyridazines / chemistry*
  • Pyridazines / pharmacology
  • Rats
  • Receptors, Histamine H3 / chemistry*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Time Factors

Substances

  • 4,5-dihydropyridazin-3-one
  • Histamine Agonists
  • Pyridazines
  • Receptors, Histamine H3