Biphenyl-3-yl alkylcarbamates as fatty acid amide hydrolase (FAAH) inhibitors: Steric effects of N-alkyl chain on rat plasma and liver stability

Secondary alkylcarbamic acid biphenyl-3-yl esters are a class of Fatty Acid Amide Hydrolase (FAAH) inhibitors, which include the reference compounds URB597 and URB694. Given the intrinsic reactivity of the carbamate group, the in vivo potency of these molecules in rats is strongly affected by their hydrolysis in plasma or hepatic metabolism. In the present study, in vitro chemical and metabolic stability assays (rat plasma and rat liver S 9 fraction) were used to investigate the structure–property relationships (SPRs) for a focused series of title compounds, where lipophilicity and steric hindrance of the carbamate N-substituent had been modulated. The resulting degradation rates indicate that a secondary or tertiary alkyl group at the carbamate nitrogen atom increases hydrolytic stability towards rat plasma esterases. The calculated solvent accessible surface area (SASA) of the carbamate fragment was employed to describe the differences observed in rate constants of hydrolysis in rat plasma (log k plasma), suggesting that stability in plasma increases if the substituent exerts a shielding effect on the carbamate carbonyl. Stability in rat liver S 9 fraction is increased when a tertiary carbon is bound to the carbamate nitrogen atom, while other steric effects showed complex relationships with degradation rates. The SPRs here described may be applied at the pharmacokinetic optimization of other classes of carbamate FAAH inhibitors. [Display omitted] ► Biphenyl-3-yl alkylcarbamates are a class of fatty acid amide hydrolase inhibitors. ► Steric effects of carbamate N-alkyl substituents can influence metabolic stability. ► Secondary or tertiary N-alkyl groups increase hydrolytic stability in rat plasma. ► Stability in rat liver S 9 fraction is increased by bulky tertiary N-alkyl groups. ► Solvent Accessible Surface Area (SASA) is a suitable descriptor of rat plasma hydrolysis.