Identification of pyridazin-3-one derivatives as potent, selective histamine H₃ receptor inverse agonists with robust wake activity

Bioorg Med Chem Lett. 2011 Sep 15;21(18):5493-7. doi: 10.1016/j.bmcl.2011.06.108. Epub 2011 Jun 30.

Abstract

H(3)R structure-activity relationships on a novel class of pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modifications of the pyridazinone core, central phenyl ring and linker led to the identification of molecules with excellent target potency, selectivity and pharmacokinetic properties. Compounds 13 and 21 displayed potent functional H(3)R antagonism in vivo in the rat dipsogenia model and demonstrated robust wake activity in the rat EEG/EMG model.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drinking / drug effects*
  • Histamine Agonists / chemical synthesis
  • Histamine Agonists / chemistry
  • Histamine Agonists / pharmacology*
  • Humans
  • Male
  • Molecular Structure
  • Pyridazines / chemical synthesis
  • Pyridazines / chemistry
  • Pyridazines / pharmacology*
  • Rats
  • Receptors, Histamine H3 / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Wakefulness / drug effects*

Substances

  • Histamine Agonists
  • Pyridazines
  • Receptors, Histamine H3