title: Synthesis and evaluation of 4- and 5-pyridazin-3-one phenoxypropylamine analogues as histamine-3 receptor antagonists.
abstract: A novel series of 4-pyridazin-3-one and 5-pyridazin-3-one analogues were designed and synthesized as H(3)R antagonists. Structure-activity relationship revealed the 5-pyridazin-3-ones 8a and S-methyl 8b had excellent human and rat H(3)R affinities, and acceptable pharmacokinetic properties. In vivo evaluation of 8a showed potent activity in the rat dipsogenia model and robust wake-promoting activity in the rat EEG/EMG model.
authors.affiliation: Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. nadinebecknell@aol.com
authors.forename: Nadine C
authors.initials: NC
authors.lastname: Becknell
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Lyons
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: Zeqi
authors.initials: Z
authors.lastname: Huang
authors.forename: John A
authors.initials: JA
authors.lastname: Gruner
authors.forename: Rita
authors.initials: R
authors.lastname: Raddatz
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
mesh_terms: D000818:Animals; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011437:Propylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C576647:4-pyridazin-3-one phenoxypropylamine; C576648:5-pyridazin-3-one phenoxypropylamine; D006633:Histamine Antagonists; D011437:Propylamines; D011724:Pyridazines; D018100:Receptors, Histamine H3