title: Synthesis and structure-activity relationship of 5-pyridazin-3-one phenoxypiperidines as potent, selective histamine H(3) receptor inverse agonists.
abstract: Optimization of the R(2) and R(6) positions of (5-{4-[3-(R)-2-methylpyrrolin-1-yl-propoxy]phenyl}-2H-pyridazin-3-one) 2a with constrained phenoxypiperidines led to the identification of 5-[4-(cyclobutyl-piperidin-4-yloxy)-phenyl]-6-methyl-2H-pyridazin-3-one 8b as a potent, selective histamine H(3) receptor antagonist with favorable pharmacokinetic properties. Compound 8b had an excellent safety genotoxocity profile for a CNS-active compound in the Ames and micronucleus tests, also displayed potent H(3)R antagonist activity in the brain in the rat dipsogenia model and robust wake activity in the rat EEG/EMG model.
authors.affiliation: Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. mtao@cephalon.com
authors.forename: Ming
authors.initials: M
authors.lastname: Tao
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: John A
authors.initials: JA
authors.lastname: Gruner
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Mathiasen
authors.forename: Zeqi
authors.initials: Z
authors.lastname: Huang
authors.forename: Jacquelyn
authors.initials: J
authors.lastname: Lyons
authors.forename: Rita
authors.initials: R
authors.lastname: Raddatz
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
mesh_terms: D000818:Animals; D006801:Humans; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D010880:Piperidines; D011724:Pyridazines; D018100:Receptors, Histamine H3