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.
Copyright © 2014 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Cognition Disorders / drug therapy
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Disease Models, Animal
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Dogs
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Drug Evaluation, Preclinical
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Drug Inverse Agonism
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Half-Life
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Haplorhini
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Memory, Short-Term / drug effects
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Nootropic Agents / chemistry*
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Nootropic Agents / pharmacokinetics
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Nootropic Agents / pharmacology
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Nootropic Agents / therapeutic use
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Piperidines / chemistry*
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Piperidines / pharmacokinetics
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Piperidines / pharmacology
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Piperidines / therapeutic use
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Pyridazines / chemistry*
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Pyridazines / pharmacokinetics
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Pyridazines / pharmacology
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Pyridazines / therapeutic use
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Rats
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Receptors, Histamine H3 / chemistry*
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Receptors, Histamine H3 / metabolism
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Stereoisomerism
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Structure-Activity Relationship
Substances
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4,5-dihydropyridazin-3-one
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5-(4-(1-cyclobutylpiperidin-4-yloxy)phenyl)-3,4-diazabicyclo(4.1.0)hept-4-en-2-one
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Nootropic Agents
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Piperidines
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Pyridazines
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Receptors, Histamine H3