title: Discovery and characterization of 6-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (CEP-26401, irdabisant): a potent, selective histamine H3 receptor inverse agonist.
abstract: Optimization of a novel series of pyridazin-3-one histamine H(3) receptor (H(3)R) antagonists/inverse agonists identified 6-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (8a, CEP-26401; irdabisant) as a lead candidate for potential use in the treatment of attentional and cognitive disorders. 8a had high affinity for both human (K(i) = 2.0 nM) and rat (K(i) = 7.2 nM) H(3)Rs with greater than 1000-fold selectivity over the hH(1)R, hH(2)R, and hH(4)R histamine receptor subtypes and against an in vitro panel of 418 G-protein-coupled receptors, ion channels, transporters, and enzymes. 8a demonstrated ideal pharmaceutical properties for a CNS drug in regard to water solubility, permeability and lipophilicity and had low binding to human plasma proteins. It weakly inhibited recombinant cytochrome P450 isoforms and human ether-a-go-go-related gene. 8a metabolism was minimal in rat, mouse, dog, and human liver microsomes, and it had good interspecies pharmacokinetic properties. 8a dose-dependently inhibited H(3)R agonist-induced dipsogenia in the rat (ED(50) = 0.06 mg/kg po). On the basis of its pharmacological, pharmaceutical, and safety profiles, 8a was selected for preclinical development. The clinical portions of the single and multiple ascending dose studies assessing safety and pharmacokinetics have been completed allowing for the initiation of a phase IIa for proof of concept.
authors.affiliation: Worldwide Discovery Research and Development, Cephalon, Inc., West Chester, Pennsylvania 19380, United States. rhudkins@cephalon.com
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
authors.forename: Rita
authors.initials: R
authors.lastname: Raddatz
authors.forename: Ming
authors.initials: M
authors.lastname: Tao
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Mathiasen
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: Nadine C
authors.initials: NC
authors.lastname: Becknell
authors.forename: Catherine P
authors.initials: CP
authors.lastname: Prouty
authors.forename: Lars J S
authors.initials: LJ
authors.lastname: Knutsen
authors.forename: Mehran
authors.initials: M
authors.lastname: Yazdanian
authors.forename: Gilbert
authors.initials: G
authors.lastname: Moachon
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ator
authors.forename: John P
authors.initials: JP
authors.lastname: Mallamo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Marino
authors.forename: Edward R
authors.initials: ER
authors.lastname: Bacon
authors.forename: Michael
authors.initials: M
authors.lastname: Williams
mesh_terms: D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D018360:Crystallography, X-Ray; D004285:Dogs; D054314:Drug Inverse Agonism; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010539:Permeability; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D006633:Histamine Antagonists; D011724:Pyridazines; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; C561238:6-(4-(3-(2-methylpyrrolidin-1-yl)propoxy)phenyl)-2H-pyridazin-3-one