4.6 Article

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

Journal

ACS OMEGA
Volume 6, Issue 20, Pages 13466-13483

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acsomega.1c01699

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A series of aryl N-[omega-(6-fluoroindol-1-yl)alkyl]-carbamates were synthesized and tested for inhibition of several important serine hydrolases. Most of the synthesized derivatives showed strong inhibition of FAAH, while some compounds also exhibited good inhibition of MAGL and BuChE. Some carbamates showed varying degrees of stability or inactivation towards esterases, with some forming covalent bonds with albumin.
A series of aryl N-[omega-(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.

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