4-Phenoxypiperidine pyridazin-3-one histamine H₃ receptor inverse agonists demonstrating potent and robust wake promoting activity
2012
Hudkins, Robert L. | Zulli, Allison L. | Dandu, Reddeppa reddy | Dao, Ming | Josef, Kurt A. | Aimone, Lisa D. | Curtis Haltiwanger, R. | Huang, Zeqi | Lyons, Jacquelyn A. | Mathiasen, Joanne R. | Raddatz, Rita | Gruner, John A.
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.
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