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Novel alpha-7 nicotinic acetylcholine receptor agonists containing a urea moiety: identification and characterization of the potent, selective, and orally efficacious agonist 1-[6-(4-fluorophenyl)pyridin-3-yl]-3-(4-piperidin-1-ylbutyl) urea (SEN34625/WYE-103914)
- Source :
- Journal of medicinal chemistry. 53(11)
- Publication Year :
- 2010
-
Abstract
- Alpha-7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment. We report a series of novel, potent small molecule agonists (4-18) of the alpha7 nAChR deriving from our continuing efforts in the areas of Alzheimer's disease and schizophrenia. One of the compounds of the series containing a urea moiety (16) was further shown to be a selective agonist of the alpha7 nAChR with excellent in vitro and in vivo profiles, brain penetration, and oral bioavailability and demonstrated in vivo efficacy in multiple behavioral cognition models. Structural modifications leading to the improved selectivity profile and the biological evaluation of this series of compounds are discussed.
- Subjects :
- Agonist
Male
Models, Molecular
alpha7 Nicotinic Acetylcholine Receptor
medicine.drug_class
Protein Conformation
Pyridines
Administration, Oral
Pharmacology
Receptors, Nicotinic
Substrate Specificity
Inhibitory Concentration 50
Structure-Activity Relationship
In vivo
Drug Discovery
medicine
Structure–activity relationship
Moiety
Animals
Humans
Urea
Nicotinic Agonists
Receptor
Chemistry
Small molecule
Rats
Nicotinic acetylcholine receptor
Nicotinic agonist
Biochemistry
Molecular Medicine
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 53
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....53e335cbea368c3d67bdfa12e50c49f4