Premium
Structure–Property Relationships of a Class of Carbamate‐Based Fatty Acid Amide Hydrolase (FAAH) Inhibitors: Chemical and Biological Stability
Author(s) -
Vacondio Federica,
Silva Claudia,
Lodola Alessio,
Fioni Alessandro,
Rivara Silvia,
Duranti Andrea,
Tontini Andrea,
Sanchini Silvano,
Clapper Jason R.,
Piomelli Daniele,
Mor Marco,
Tarzia Giorgio
Publication year - 2009
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200900120
Subject(s) - fatty acid amide hydrolase , chemistry , carbamate , moiety , homo/lumo , amide , aryl , stereochemistry , structure–activity relationship , conjugated system , organic chemistry , biochemistry , in vitro , molecule , alkyl , receptor , cannabinoid receptor , agonist , polymer
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.