Document Detail


Discovery and structure-activity relationship of a novel spirocarbamate series of NPY Y5 antagonists.
MedLine Citation:
PMID:  20813523     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 3mg/kg po.
Authors:
Colin P Leslie; Jonathan Bentley; Matteo Biagetti; Stefania Contini; Romano Di Fabio; Daniele Donati; Thorsten Genski; Sebastien Guery; Angelica Mazzali; Giancarlo Merlo; Domenica A Pizzi; Fabiola Sacco; Catia Seri; Michela Tessari; Laura Zonzini; Laura Caberlotto
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Publication Detail:
Type:  Journal Article     Date:  2010-08-12
Journal Detail:
Title:  Bioorganic & medicinal chemistry letters     Volume:  20     ISSN:  1464-3405     ISO Abbreviation:  Bioorg. Med. Chem. Lett.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-09-20     Completed Date:  2011-01-13     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9107377     Medline TA:  Bioorg Med Chem Lett     Country:  England    
Other Details:
Languages:  eng     Pagination:  6103-7     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Ltd. All rights reserved.
Affiliation:
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline SpA, Medicines Research Centre, Verona, Italy. colin.p.leslie@gsk.com
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MeSH Terms
Descriptor/Qualifier:
Animals
Carbamates / chemistry*,  metabolism,  pharmacokinetics,  pharmacology*
Cell Line
Cytochrome P-450 Enzyme System / antagonists & inhibitors,  metabolism
Humans
Microsomes, Liver / metabolism
Rats
Receptors, Neuropeptide Y / antagonists & inhibitors*,  metabolism*
Spiro Compounds / chemistry*,  metabolism,  pharmacokinetics,  pharmacology*
Structure-Activity Relationship
Chemical
Reg. No./Substance:
0/Carbamates; 0/Receptors, Neuropeptide Y; 0/Spiro Compounds; 9035-51-2/Cytochrome P-450 Enzyme System

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