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

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

Synthesis and Quantitative Structure-Activity Relationship of Fatty Acid Amide Hydrolase Inhibitors: Modulation at the N-Portion of Biphenyl-3-yl Alkylcarbamates.

Alkylcarbamic acid biphenyl-3-yl esters are a class of fatty acid amide hydrolase (FAAH) inhibitors that comprises cyclohexylcarbamic acid 3′-carbamoylbiphenyl-3-yl ester (URB597), a compound with analgesic, anxiolytic-like and antidepressant-like properties in rat and mouse models. Here, we extended the structure-activity relationships (SARs) for this class of compounds by replacing the cyclohexyl ring of the parent compound cyclohexylcarbamic acid biphenyl-3-yl ester (URB524) (FAAH IC50: 63 nM) with a selected set of substituents of different size, shape, flexibility, and lipophilicity. Docking experiments and linear interaction energy (LIE) calculations indicated that the N-terminal group of O-arylcarbamates fits within the lipophilic region of the substrate-binding site, mimicking the arachidonoyl chain of anandamide. Significant potency improvements were observed for the beta-naphthylmethyl derivative 4q (IC50 ) 5.3 nM) and its 3′-carbamoylbiphenyl-3-yl ester 4z (URB880, IC50 ) 0.63 nM), indicating that shape complementarity and hydrogen bonds are crucial to obtain highly potent inhibitors

Experimental approaches to study the nutritional value of food ingredients for dogs and cats

This review covers methods that have been applied to study the nutrient value or quality of specific ingredients fed to dogs, cats and comparable species (i.e. foxes, minks, rats, etc.). Typically, the nutritional value or utilization of a specific ingredient is measured by total tract digestibility and has been expanded through the measurement of total nutrient balance (i.e. nitrogen or energy). However, to better understand digestion it is necessary to obtain a more accurate measurement of nutrients entering and leaving the small intestine. Accurate measurement of small intestinal digestion is crucial in dogs and cats because nutrient digestion and absorption occurs primarily in the small intestine. Measuring small intestinal digestibility requires access to digesta leaving the small intestine and can be obtained by placing a cannula at the terminal ileum. This approach also necessitates the use of markers (e.g. chromic oxide) to monitor flow of digesta. Specifically, this approach has been used for the direct measurement of intestinal digestion of carbohydrates and amino acids. It also permits a separate measurement of large intestinal digestion which is particularly useful for the study of fiber fermentation. Passage of foods through the gastrointestinal tract is also an important component of utilization and these methods are reviewed