Controlling elevated tissue-specific levels of cortisol may provide a novel therapeutic approach for treating metabolic syndrome. This concept has spurred large scale medicinal chemistry efforts in the pharmaceutical industry for the design of 11β-HSD1 inhibitors. High resolution X-ray crystal structures of inhibitors in complex with the enzyme have facilitated the structure-based design of diverse classes of molecules. A summary of binding modes, trends in structure- activity relationships, and the pharmacodynamic data of inhibitors from each class is presented.
Keywords: Metabolic syndrome, 11β-HSD1, inhibitors, structure-based drug design, x-ray crystal structures, binding modes, structure-activity relationship, natural products, cortisone, cortisol, triazoles, aminothiazolones, sulfonamides, pharmacodynamic, hypothalamic-pituitary-adrenal axis, 11-hydroxyste-roid dehydrogenase types 1 and 2, 11-keto group, glucocorticoid cortisone 1, Q177Y, I180V, I227V, E226A, whole body inhibition, tissue specific in-hibition, short-chain alcohol dehydrogenase/reductase, triterpene 18-glycyrrhetinic acid, Carbenoxolone, Triazole, cyclopropyl-4-fluorobenzyl group, 18-glycyrrhetinic acid, polar 4-(2-pyridyl)piperazin-1-yl, amide carbonyl oxygen, Ser170, Tyr183 phenol, 3-fluoro-4-methyl substitution, cyclo-octylamino compound, benzylamino compounds, Leu171, aminothiazolone ring, thiazolone ring, AMG-221, sulfonamide, (2-hydroxy-1,1,1-trifluoro)-2-propyl group, CYP3A4 inhibitor
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