Journal article
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 H-3 Receptor Inverse Agonist
Journal of medicinal chemistry, v 54(13), pp 4781-4792
14 Jul 2011
PMID: 21634396
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Optimization of a novel series of pyridazin-3-one histamine H-3 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) 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 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 Ha for proof of concept
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Details
- 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 H-3 Receptor Inverse Agonist
- Creators
- Robert L. Hudkins - Cephalon Inc, Worldwide Discovery Res & Dev, W Chester, PA 19380 USARita Raddatz - Cephalon Inc, Worldwide Discovery Res & Dev, W Chester, PA 19380 USAMing Tao - Cephalon Inc, Worldwide Discovery Res & Dev, W Chester, PA 19380 USAJoanne R. Mathiasen - Cephalon Inc, Worldwide Discovery Res & Dev, W Chester, PA 19380 USALisa D. Aimone - Cephalon Inc, Worldwide Discovery Res & Dev, W Chester, PA 19380 USANadine C. Becknell - Cephalon Inc, Worldwide Discovery Res & Dev, W Chester, PA 19380 USACatherine P. Prouty - Cephalon Inc, Worldwide Discovery Res & Dev, W Chester, PA 19380 USALars J. S. Knutsen - Cephalon Inc, Worldwide Discovery Res & Dev, W Chester, PA 19380 USAMehran Yazdanian - Cephalon Inc, Worldwide Discovery Res & Dev, W Chester, PA 19380 USAGilbert Moachon - Cephalon Inc, Maisons Alfort, FranceMark A. Ator - Cephalon Inc, Worldwide Discovery Res & Dev, W Chester, PA 19380 USAJohn P. Mallamo - Cephalon Inc, Worldwide Discovery Res & Dev, W Chester, PA 19380 USAMichael J. Marino - Cephalon Inc, Worldwide Discovery Res & Dev, W Chester, PA 19380 USAEdward R. Bacon - Cephalon Inc, Worldwide Discovery Res & Dev, W Chester, PA 19380 USAMichael Williams - Cephalon Inc, Worldwide Discovery Res & Dev, W Chester, PA 19380 USA
- Publication Details
- Journal of medicinal chemistry, v 54(13), pp 4781-4792
- Publisher
- Amer Chemical Soc
- Number of pages
- 12
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000292479600035
- Scopus ID
- 2-s2.0-79960169443
- Other Identifier
- 991021900195204721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal