title: Identification of pyridazin-3-one derivatives as potent, selective histamine H₃ receptor inverse agonists with robust wake activity.
abstract: H(3)R structure-activity relationships on a novel class of pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modifications of the pyridazinone core, central phenyl ring and linker led to the identification of molecules with excellent target potency, selectivity and pharmacokinetic properties. Compounds 13 and 21 displayed potent functional H(3)R antagonism in vivo in the rat dipsogenia model and demonstrated robust wake 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: Thomas R
authors.initials: TR
authors.lastname: Bailey
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bendesky
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: Kurt A
authors.initials: KA
authors.lastname: Josef
authors.forename: Yin-Guo
authors.initials: YG
authors.lastname: Lin
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Lyons
authors.forename: Val R
authors.initials: VR
authors.lastname: Marcy
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Mathiasen
authors.forename: Babu G
authors.initials: BG
authors.lastname: Sundar
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
authors.forename: Edward R
authors.initials: ER
authors.lastname: Bacon
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects*; D017442:Histamine Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D015394:Molecular Structure; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018100:Receptors, Histamine H3 / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014851:Wakefulness / Q000187:drug effects*
chemical_list: D017442:Histamine Agonists; D011724:Pyridazines; D018100:Receptors, Histamine H3