Discovery of spiropiperidine-based potent and selective Orexin-2 receptor antagonists

To generate novel human Orexin-2 Receptor (OX2R) antagonists, a spiropiperidine based scaffold was designed and a SAR study was carried out. Compound 4f possessed the highest OX2R antagonistic activity with an IC50 value of 3 nM with 450-fold selectivity against Orexin-1 Receptor (OX1R). To generate...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-11, Vol.21 (21), p.6409-6413
Hauptverfasser:	Fujimoto, Tatsuhiko, Tomata, Yoshihide, Kunitomo, Jun, Hirozane, Mariko, Marui, Shogo
Format:	Artikel
Sprache:	eng
Schlagworte:	antagonists Biological and medical sciences chemistry Drug Discovery humans Hypnotics. Sedatives inhibitory concentration 50 Insomnia Ligands Medical sciences Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Orexin Receptors Orexin-2 receptor antagonists Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Piperidines - chemistry Piperidines - pharmacology Psychology. Psychoanalysis. Psychiatry Psychopharmacology Receptors, G-Protein-Coupled - antagonists & inhibitors Receptors, Neuropeptide - antagonists & inhibitors Sleep disorder Spiropiperidine
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Zusammenfassung:	To generate novel human Orexin-2 Receptor (OX2R) antagonists, a spiropiperidine based scaffold was designed and a SAR study was carried out. Compound 4f possessed the highest OX2R antagonistic activity with an IC50 value of 3 nM with 450-fold selectivity against Orexin-1 Receptor (OX1R). To generate novel human Orexin-2 Receptor (OX2R) antagonists, a spiropiperidine based scaffold was designed and a SAR study was carried out. Compound 4f possessed the highest OX2R antagonistic activity with an IC 50 value of 3 nM with 450-fold selectivity against Orexin-1 Receptor (OX1R).
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.08.094