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ω‐Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase
Author(s) -
Dato Florian M.,
Sheikh Miriam,
Uhl Rocky Z.,
Schüller Alexandra W.,
Steinkrüger Michaela,
Koch Peter,
Neudörfl JörgMartin,
Gütschow Michael,
Goldfuss Bernd,
Pietsch Markus
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800388
Subject(s) - phthalimide , trifluoromethyl , chemistry , aryl , monoacylglycerol lipase , urea , stereochemistry , serine hydrolase , amide , enzyme , serine , hydrolase , esterase , fatty acid amide hydrolase , alkyl , biochemistry , organic chemistry , agonist , endocannabinoid system , receptor , cannabinoid receptor
Cholesterol esterase (CEase), a serine hydrolase thought to be involved in atherogenesis and thus coronary heart disease, is considered as a target for inhibitor development. We investigated recombinant human and murine CEases with a new fluorometric assay in a structure–activity relationship study of a small library of ω‐phthalimidoalkyl aryl ureas. The urea motif with an attached 3,5‐bis(trifluoromethyl)phenyl group and the aromatic character of the ω‐phthalimide residue were most important for inhibitory activity. In addition, an alkyl chain composed of three or four methylene groups, connecting the urea and phthalimide moieties, was found to be an optimal spacer for inhibitors. The so‐optimized compounds 2 [1‐(3,5‐bis(trifluoromethyl)phenyl)‐3‐(3‐(1,3‐dioxoisoindolin‐2‐yl)propyl)urea] and 21 [1‐(3,5‐bis(trifluoromethyl)phenyl)‐3‐(4‐(1,3‐dioxoisoindolin‐2‐yl)butyl)urea] exhibited dissociation constants ( K i ) of 1–19 μ m on the two CEases and showed either a competitive ( 2 on the human enzyme and 21 on the murine enzyme) or a noncompetitive mode of inhibition. Two related serine hydrolases—monoacylglycerol lipase and fatty acid amide hydrolase—were inhibited by ω‐phthalimidoalkyl aryl ureas to a lesser extent.