4-Phenoxypiperidine pyridazin-3-one histamine H3 receptor inverse agonists demonstrating potent and robust wake promoting activity

Structure–activity relationships for a series of phenoxypiperidine pyridazin-3-one H3R 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)-phen...

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Published in:Bioorganic & medicinal chemistry letters 2012-02, Vol.22 (4), p.1504-1509
Main Authors: Hudkins, Robert L., Zulli, Allison L., Dandu, Reddeppa reddy, Tao, Ming, Josef, Kurt A., Aimone, Lisa D., Curtis Haltiwanger, R., Huang, Zeqi, Lyons, Jacquelyn A., Mathiasen, Joanne R., Raddatz, Rita, Gruner, John A.
Format: Article
Language:English
Subjects:
agonists
antagonists
Biological and medical sciences
CEP-26401
electroencephalography
electromyography
H3 inverse agonist
histamine
Histamine H3 receptor
Irdabisant
Medical sciences
metabolites
Pharmacology. Drug treatments
Pyridazin-3-one
rats
Sleep–wake
structure-activity relationships
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Summary:Structure–activity relationships for a series of phenoxypiperidine pyridazin-3-one H3R 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 H3R functional antagonism in vivo in the rat dipsogenia model and potent wake activity in the rat EEG/EMG model at doses as low as 0.1mg/kg ip.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.01.026