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 Inv

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• 作者：Robert L. Hudkins ; Rita Raddatz ; Ming Tao ; Joanne R. Mathiasen ; Lisa D. Aimone ; Nadine C. Becknell ; Catherine P. Prouty ; Lars J. S. Knutsen ; Mehran Yazdanian ; Gilbert Moachon ; Mark A. Ator ; John P. Mallamo ; Michael J. Marino ; Edward R. Bacon ; Michael Williams
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 14, 2011
• 年：2011
• 卷：54
• 期：13
• 页码：4781-4792
• 全文大小：1007K
• 年卷期：v.54,no.13(July 14, 2011)
• ISSN：1520-4804

文摘

Optimization of a novel series of pyridazin-3-one histamine H₃ receptor (H₃R) 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) H₃Rs with greater than 1000-fold selectivity over the hH₁R, hH₂R, and hH₄R 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 H₃R agonist-induced dipsogenia in the rat (ED₅₀ = 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.