title: 4-phenoxypiperidine pyridazin-3-one histamine H(3) receptor inverse agonists demonstrating potent and robust wake promoting activity.
abstract: 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.
authors.affiliation: Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. rhudkins@cephalon.com
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
authors.forename: Allison L
authors.initials: AL
authors.lastname: Zulli
authors.forename: Reddeppa reddy
authors.initials: Rr
authors.lastname: Dandu
authors.forename: Ming
authors.initials: M
authors.lastname: Tao
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Josef
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: R Curtis
authors.initials: RC
authors.lastname: Haltiwanger
authors.forename: Zeqi
authors.initials: Z
authors.lastname: Huang
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Lyons
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Mathiasen
authors.forename: Rita
authors.initials: R
authors.lastname: Raddatz
authors.forename: John A
authors.initials: JA
authors.lastname: Gruner
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006633:Histamine Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D011724:Pyridazines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D018100:Receptors, Histamine H3; D014851:Wakefulness / Q000187:drug effects*
chemical_list: C572256:6-(4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl)-4,4-dimethyl-4,5-dihydro-2H-pyridazin-3-one; D006633:Histamine Antagonists; D010880:Piperidines; D011724:Pyridazines; D018100:Receptors, Histamine H3