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N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis, Structure-Activity and Structure-Property Relationships.
MedLine Citation:
PMID:  22515328     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The ß-lactone ring of N-(2-oxo-3-oxetanyl)amides, a class of N-acylethanolamine acid amidase (NAAA) inhibitors endowed with anti-inflammatory properties, is responsible for both NAAA inhibition and low compound stability. Here, we investigated the structure-activity and structure-property relationships for a set of known and new ß-lactone derivatives, focusing on the new class of N-(2-oxo-3-oxetanyl)carbamates. Replacement of the amide group with a carbamate one led to different stereoselectivity for NAAA inhibition and higher intrinsic stability, due to reduced intramolecular attack at the lactone ring. The introduction of a syn methyl at the ß-position of the lactone further improved chemical stability. A tert-butyl substituent in the side chain reduced the reactivity with bovine serum albumin. (2S,3R)-2-methyl-4-oxo-3-oxetanylcarbamic acid 5-phenylpentyl ester (27, URB913/ARN077) inhibited NAAA with good in vitro potency (IC50 = 127 nM) and showed improved stability. It is rapidly cleaved in plasma, which supports its use for topical applications.
Authors:
Andrea Duranti; Andrea Tontini; Francesca Antonietti; Federica Vacondio; Alessandro Fioni; Claudia Silva; Alessio Lodola; Silvia Rivara; Carlos Solorzano; Daniele Piomelli; Giorgio Tarzia; Marco Mor
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-4-19
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  -     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-4-20     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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