title: Substituted phenoxypropyl-(R)-2-methylpyrrolidine aminomethyl ketones as histamine-3 receptor inverse agonists.
abstract: Optimization of a series of aminomethyl ketone diamine H(3)R antagonists to reduce the brain exposure by lowering the pKa, led to molecules with improved pharmacokinetic properties. Compounds 9, 19, and 25 had high affinity for human H(3)R and demonstrated in vivo H(3)R functional activity in the rat dipsogenia model. Compound 9 displayed modest wake-promoting activity in the rat EEG/EMG model.
authors.affiliation: Discovery Research, Cephalon, Inc., West Chester, PA 19380, USA. azulli@cephalon.com
authors.forename: Allison L
authors.initials: AL
authors.lastname: Zulli
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Mathiasen
authors.forename: John A
authors.initials: JA
authors.lastname: Gruner
authors.forename: Rita
authors.initials: R
authors.lastname: Raddatz
authors.forename: Edward R
authors.initials: ER
authors.lastname: Bacon
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
mesh_terms: D000433:1-Propanol / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D054314:Drug Inverse Agonism; D017442:Histamine Agonists / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007659:Ketones / Q000737:chemistry* / Q000494:pharmacology; D008744:Methylamines / Q000737:chemistry / Q000494:pharmacology; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D020178:Sleep Disorders, Circadian Rhythm / Q000188:drug therapy; D014851:Wakefulness / Q000187:drug effects*
chemical_list: D017442:Histamine Agonists; D007659:Ketones; D008744:Methylamines; D010636:Phenols; D011759:Pyrrolidines; C042329:phenoxy radical; D000433:1-Propanol; C027451:methylamine; C032519:pyrrolidine