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

Autor: Hudkins RL; Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. rhudkins@cephalon.com, Zulli AL, Dandu Rr, Tao M, Josef KA, Aimone LD, Haltiwanger RC, Huang Z, Lyons JA, Mathiasen JR, Raddatz R, Gruner JA
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2012 Feb 15; Vol. 22 (4), pp. 1504-9. Date of Electronic Publication: 2012 Jan 13.
DOI: 10.1016/j.bmcl.2012.01.026
Abstrakt: 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.
(Copyright © 2012 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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