title: 4,5-dihydropyridazin-3-one derivatives as histamine H₃ receptor inverse agonists.
abstract: H(3)R structure-activity relationships for a new class of 4,5-dihydropyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modification of the 4,5-dihydropyridazinone moiety to block in vivo metabolism identified 4,4-dimethyl-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4,5-dihydro-2H-pyridazin-3-one 22 as a lead candidate demonstrating potent in vivo functional H(3)R antagonism 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. rhudkins@cephalon.com
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: Reddeppa Reddy
authors.initials: RR
authors.lastname: Dandu
authors.forename: Derek
authors.initials: D
authors.lastname: Dunn
authors.forename: John A
authors.initials: JA
authors.lastname: Gruner
authors.forename: Zeqi
authors.initials: Z
authors.lastname: Huang
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Josef
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Lyons
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Mathiasen
authors.forename: Ming
authors.initials: M
authors.lastname: Tao
authors.forename: Allison L
authors.initials: AL
authors.lastname: Zulli
authors.forename: Rita
authors.initials: R
authors.lastname: Raddatz
mesh_terms: D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004569:Electroencephalography / Q000379:methods; D004576:Electromyography / Q000379:methods; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D008956:Models, Chemical; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: C573777:4,5-dihydropyridazin-3-one; D017442:Histamine Agonists; D011724:Pyridazines; D018100:Receptors, Histamine H3