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
posted on 2021-05-14, 13:33authored byStefan Rudolph, Helmut Dahlhaus, Walburga Hanekamp, Christian Albers, Maximilian Barth, Giulia Michels, Denise Friedrich, Matthias Lehr
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.