4-phenoxypiperidine pyridazin-3-one histamine H(3) receptor inverse agonists demonstrating potent and robust wake promoting activity

Bioorg Med Chem Lett. 2012 Feb 15;22(4):1504-9. doi: 10.1016/j.bmcl.2012.01.026. Epub 2012 Jan 13.

Abstract

Structure-activity relationships for a series of phenoxypiperidine pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. The search for compounds with improved hERG and DAT selectivity without the formation of in vivo active metabolites identified 6-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-4,4-dimethyl-4,5-dihydro-2H-pyridazin-3-one 17b. Compound 17b met discovery flow criteria, demonstrated potent H(3)R functional antagonism in vivo in the rat dipsogenia model and potent wake activity in the rat EEG/EMG model at doses as low as 0.1 mg/kg ip.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Histamine Antagonists / chemistry*
  • Histamine Antagonists / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Piperidines / chemistry*
  • Piperidines / pharmacology
  • Pyridazines / chemistry*
  • Pyridazines / pharmacology
  • Rats
  • Receptors, Histamine H3*
  • Wakefulness / drug effects*

Substances

  • 6-(4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl)-4,4-dimethyl-4,5-dihydro-2H-pyridazin-3-one
  • Histamine Antagonists
  • Piperidines
  • Pyridazines
  • Receptors, Histamine H3