Aryl N-[ω-(6-Fluoroindol-1-yl)alkyl]carbamates as Inhibitors of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and Butyrylcholinesterase: Structure-Activity Relationships and Hydrolytic Stability.

A series of aryl N-[ω-(6-fluoroindol-1-yl)alkyl]carbamates with alkyl spacers of varying lengths between the indole and the carbamate group and with differently substituted aryl moieties at the carbamate oxygen were synthesized and tested for inhibition of the pharmacologically interesting serine hydrolases fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), butyrylcholinesterase (BuChE), and acetylcholinesterase (AChE). Furthermore, the chemical stability in an aqueous solution and the metabolic stability toward esterases in porcine liver homogenate and porcine blood plasma were determined. While most of the synthesized derivatives were potent inhibitors of FAAH, a considerable inhibition of MAGL and BuChE was elicited only by compounds with a high carbamate reactivity, as evidenced by a significant hydrolysis of these compounds in an aqueous solution. However, the high inhibitory potency of some compounds toward MAGL and BuChE, especially that of the ortho-carboxyphenyl derivative 37, could not be explained by chemical reactivity alone. Several of the carbamates studied possessed varying degrees of stability toward esterases from liver and blood plasma. In some cases, marked inactivation by the pseudo-esterase activity of plasma albumin was observed. Mass spectrometric studies showed that such carbamates formed covalent bonds with albumin at several sites.

(Indolylalkyl)piperidine carbamates as inhibitors of fatty acid amide hydrolase (FAAH).

A series of phenyl 4-[(indol-1-yl)alkyl]piperidine carbamates was synthesized and tested for inhibition of the endocannabinoid degrading enzyme fatty acid amide hydrolase (FAAH) and for metabolic stability in rat liver S9 fractions and porcine blood plasma. Structure-activity relationship studies revealed that variation of the length of the alkyl spacer connecting the indole and the piperidine heterocycle, introduction of substituents into the indole ring, replacement of the piperidine by a piperazine scaffold as well as opening of the piperidine ring system affect activity significantly. The metabolic stability of this compound class proved to be significantly higher than that of corresponding phenyl N-(indol-1-ylalkyl)carbamates.