Discovery and biological evaluation of adamantyl amide 11β-HSD1 inhibitors
Graphical abstract
The synthesis and biological activity of a series of adamantyl amide 11β-HSD1 inhibitors represented by 5 is reported.
Section snippets
Acknowledgments
We thank Enamine Ltd for the provision of synthetic chemistry services and the Wellcome Trust for funding.
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2018, Bioorganic ChemistryCitation Excerpt :The predicted positions of the ligands docked into 11β-HSD1 were characterized by a simultaneous lowering of the scoring function value, Docking Score [kJ/mol]; this corresponds to the high values of the ligand binding energy. In order to search for effective and selective inhibitors of 11β-HSD1, attention was paid to thiazole derivatives i.a. BVT-14225, BVT-2733, BVT-3498 [3,18], 2-amino-1,3-thiazol-4(5H)one [5,19,20], (1,3-benzothiazol-2-yl)benzenesulfonamides [21] and adamantyl amides [1]. The possibility of using thiazolo[3,2-a]pyrimidine-5-one derivatives as inhibitors of 11β-HSD1 have not been earlier studied and reported in the literature.
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2013, Biochemical PharmacologyCitation Excerpt :Inter-conversion of substrates and products was quantified under conditions of first order kinetics. Three forms of murine enzyme (n = 6/group) were used: (1) a truncated form of recombinant m11βHSD1 protein (N23Δ, gift from Dr Webster), (2) enzyme contained within murine hepatic microsomes and (3) a full-length m11βHSD1 protein expressed in stably transfected HEK293 cells [24]. Recombinant (14–28 μg/mL) or murine hepatic microsomal (240–260 μg/mL [19]) protein was incubated (30 min, 37 °C) with 7-oxysterols (0.02–20 μM) in potassium phosphate buffer (0.1 M, 0.1 mM EDTA, 20 mM cysteamine hydrochloride, pH 7.4), or with steroids (0.02–20 μM) in Krebs-Ringer buffer (containing 5 mM glucose), and the relevant cofactor (2 mM) for oxidation (NADP+ or NAD+) or reduction (NADPH or NADH).