Discovery of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a): histamine H(3) receptor inverse agonist demonstrating potent cognitive enhancing and wake promoting activity

Bioorg Med Chem Lett. 2014 Mar 1;24(5):1303-6. doi: 10.1016/j.bmcl.2014.01.061. Epub 2014 Jan 30.

Abstract

A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-generation pyridazin-3-one H3R antagonist. Compound R,S-4a was a potent H3R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model, and enhanced short-term memory in the rat social recognition memory model at doses as low as 0.03-0.3 mg/kg po.

Keywords: CEP-26401; Cognition; H(3) inverse agonist; Histamine H(3) receptor; Pyridazin-3-one; Sleep–wake.

MeSH terms

  • Animals
  • Cognition Disorders / drug therapy
  • Disease Models, Animal
  • Dogs
  • Drug Evaluation, Preclinical
  • Drug Inverse Agonism
  • Half-Life
  • Haplorhini
  • Memory, Short-Term / drug effects
  • Nootropic Agents / chemistry*
  • Nootropic Agents / pharmacokinetics
  • Nootropic Agents / pharmacology
  • Nootropic Agents / therapeutic use
  • Piperidines / chemistry*
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology
  • Piperidines / therapeutic use
  • Pyridazines / chemistry*
  • Pyridazines / pharmacokinetics
  • Pyridazines / pharmacology
  • Pyridazines / therapeutic use
  • Rats
  • Receptors, Histamine H3 / chemistry*
  • Receptors, Histamine H3 / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 4,5-dihydropyridazin-3-one
  • 5-(4-(1-cyclobutylpiperidin-4-yloxy)phenyl)-3,4-diazabicyclo(4.1.0)hept-4-en-2-one
  • Nootropic Agents
  • Piperidines
  • Pyridazines
  • Receptors, Histamine H3