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Discovery, synthesis, selectivity modulation and DMPK characterization of 5-azaspiro[2.4]heptanes as potent orexin receptor antagonists.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2013 May 01; Vol. 23 (9), pp. 2653-8. Date of Electronic Publication: 2013 Mar 01. - Publication Year :
- 2013
-
Abstract
- Starting from a orexin 1 receptor selective antagonist 4,4-disubstituted piperidine series a novel potent 5-azaspiro[2.4]heptane dual orexin 1 and orexin 2 receptor antagonist class has been discovered. SAR and Pharmacokinetic optimization of this series is herein disclosed. Lead compound 15 exhibits potent activity against orexin 1 and orexin 2 receptors along with low cytochrome P450 inhibition potential, good brain penetration and oral bioavailability in rats.<br /> (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Biological Availability
Brain drug effects
Brain metabolism
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 Enzyme System metabolism
Drug Evaluation, Preclinical
Half-Life
Heptanes chemical synthesis
Heptanes pharmacokinetics
Orexin Receptors
Rats
Receptors, G-Protein-Coupled metabolism
Receptors, Neuropeptide metabolism
Structure-Activity Relationship
Aza Compounds chemistry
Heptanes chemistry
Receptors, G-Protein-Coupled antagonists & inhibitors
Receptors, Neuropeptide antagonists & inhibitors
Spiro Compounds chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 23
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 23535328
- Full Text :
- https://doi.org/10.1016/j.bmcl.2013.02.093