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ChemMedChem. 2009 Sep;4(9):1495-504. doi: 10.1002/cmdc.200900120.

Structure-property relationships of a class of carbamate-based fatty acid amide hydrolase (FAAH) inhibitors: chemical and biological stability.

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Dipartimento Farmaceutico, Università degli Studi di Parma, Viale G. P. Usberti 27A, Campus Universitario, 43100 Parma, Italy.


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.

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