Document Detail


Structure-property relationships of a class of carbamate-based fatty acid amide hydrolase (FAAH) inhibitors: chemical and biological stability.
MedLine Citation:
PMID:  19554599     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cyclohexylcarbamic acid aryl esters are a class of fatty acid amide hydrolase (FAAH) inhibitors, which includes the reference compound URB597. The reactivity of their carbamate fragment is involved in pharmacological activity and may affect their pharmacokinetic and toxicological properties. We conducted in vitro stability experiments in chemical and biological environments to investigate the structure-stability relationships in this class of compounds. The results show that electrophilicity of the carbamate influences chemical stability, as suggested by the relation between the rate constant of alkaline hydrolysis (log k(pH9)) and the energy of the lowest unoccupied molecular orbital (LUMO). Introduction of small electron-donor substituents at conjugated positions of the O-aryl moiety increased the overall hydrolytic stability of the carbamate group without affecting FAAH inhibitory potency, whereas peripheral non-conjugated hydrophilic groups, which favor FAAH recognition, helped decrease oxidative metabolism in the liver.
Authors:
Federica Vacondio; Claudia Silva; Alessio Lodola; Alessandro Fioni; Silvia Rivara; Andrea Duranti; Andrea Tontini; Silvano Sanchini; Jason R Clapper; Daniele Piomelli; Marco Mor; Giorgio Tarzia
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  ChemMedChem     Volume:  4     ISSN:  1860-7187     ISO Abbreviation:  ChemMedChem     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-01     Completed Date:  2009-12-29     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  101259013     Medline TA:  ChemMedChem     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  1495-504     Citation Subset:  IM    
Affiliation:
Dipartimento Farmaceutico, Università degli Studi di Parma, Viale G. P. Usberti 27A, Campus Universitario, 43100 Parma, Italy.
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MeSH Terms
Descriptor/Qualifier:
Amidohydrolases / antagonists & inhibitors*,  metabolism
Animals
Carbamates / chemistry*,  pharmacology
Drug Stability
Enzyme Inhibitors / chemistry*,  pharmacology
Half-Life
Male
Rats
Rats, Wistar
Structure-Activity Relationship
Grant Support
ID/Acronym/Agency:
R01 DA012413/DA/NIDA NIH HHS
Chemical
Reg. No./Substance:
0/Carbamates; 0/Enzyme Inhibitors; EC 3.5.-/Amidohydrolases; EC 3.5.1.-/fatty-acid amide hydrolase
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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