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Design, synthesis, and structure–activity relationships of a series of novel N-aryl-2-phenylcyclopropanecarboxamide that are potent and orally active orexin receptor antagonists
- Source :
- Bioorganic & Medicinal Chemistry. 22:6071-6088
- Publication Year :
- 2014
- Publisher :
- Elsevier BV, 2014.
-
Abstract
- Herein we describe the design, synthesis, and structure–activity relationships (SARs) of a novel phenylcyclopropane series represented by 7 and 33b as antagonists of orexin 1 and orexin 2 receptors. With 4 serving as the initial lead for the development of orexin antagonists, exploration of SAR resulted in improved binding affinity for orexin 1 and orexin 2 receptors. Among the synthesized compounds, 33b ((−)-N-(5-cyanopyridin-2-yl)-2-[(3,4-dimethoxyphenyl)oxymethyl]-2-phenylcyclopropanecarboxamide) exhibited potent in vitro activity and oral efficacy in animal sleep measurement experiments. The results of our study suggest that compound 33b may serve as a valuable template for the development of new orexin receptor antagonists.
- Subjects :
- Cyclopropanes
Male
Models, Molecular
Clinical Biochemistry
Pharmaceutical Science
Pharmacology
Biochemistry
Sleep measurement
Mice
Structure-Activity Relationship
chemistry.chemical_compound
Orexin Receptors
Sleep Initiation and Maintenance Disorders
mental disorders
Drug Discovery
Animals
Humans
Receptor
Molecular Biology
Orexin Receptor Antagonists
Aryl
digestive, oral, and skin physiology
Organic Chemistry
In vitro
Orexin
Mice, Inbred C57BL
Orally active
nervous system
chemistry
Design synthesis
Drug Design
Molecular Medicine
Sleep
hormones, hormone substitutes, and hormone antagonists
psychological phenomena and processes
Subjects
Details
- ISSN :
- 09680896
- Volume :
- 22
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....c68b77e7ee43866e9d8c7d2ad6a22b53