Discovery and structure–activity relationship of a novel spirocarbamate series of NPY Y5 antagonists

• Published in: Bioorganic & medicinal chemistry letters 2010-10, Vol.20 (20), p.6103-6107
• Main Authors: Leslie, Colin P., Bentley, Jonathan, Biagetti, Matteo, Contini, Stefania, Di Fabio, Romano, Donati, Daniele, Genski, Thorsten, Guery, Sebastien, Mazzali, Angelica, Merlo, Giancarlo, Pizzi, Domenica A., Sacco, Fabiola, Seri, Catia, Tessari, Michela, Zonzini, Laura, Caberlotto, Laura
• Format: Article
• Language: English
• Subjects: Animals; Antagonists; Biological and medical sciences; Carbamates - chemistry; Carbamates - metabolism; Carbamates - pharmacokinetics; Carbamates - pharmacology; Cell Line; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; Humans; Medical sciences; Microsomes, Liver - metabolism; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; NPY Y5; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Rats; Receptors, Neuropeptide Y - antagonists & inhibitors; Receptors, Neuropeptide Y - metabolism; Spiro Compounds - chemistry; Spiro Compounds - metabolism; Spiro Compounds - pharmacokinetics; Spiro Compounds - pharmacology; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.08.041

The synthesis and SAR of a series of potent NPY Y5 antagonists is reported. Optimization led to the identification of compounds 23p and 23u (fpKi = 10.0). A novel series of trans-8-aminomethyl-1-oxa-3-azaspiro[4.5]decan-2-one derivatives was identified with potent NPY Y5 antagonist activity. Optimization of the original lead furnished compounds 23p and 23u, which combine sub-nanomolar Y5 activity with metabolic stability, oral bioavailability, brain penetration and strong preclinical profile for development. Both compounds significantly inhibited the food intake induced by a Y5 selective agonist with minimal effective doses of 3 mg/kg po.