Synthesis and optimization of arylsulfonylpiperazines as a novel class of inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)
Graphical abstract
The synthesis and SAR of a series of arylsulfonylpiperazine inhibitors of 11β-HSD1 are described. Optimization rapidly led to potent, selective, and orally bioavailable inhibitors demonstrating efficacy in a cynomolgus monkey ex vivo enzyme inhibition model.
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2020, Bioorganic ChemistryCitation Excerpt :Water solubility was elevated to more than 48 μg/mL from 0.5 μg/mL of compound 22 in pH 5.0 solution as expected, the oral bioavailability was improved to 41% in rats. Best of all, it showed good efficacy in cynomolgus monkey ex vivo pharmacodynamic model measured by lowering 11β-HSD1 adipose activity [88]. The IC50 values towards 11β-HSD1 enzyme and 11β-HSD1 adipocyte of carbamate-bearing compound 24 (Fig. 5) were 5 nM and 53 nM respectively.
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2014, Bioorganic and Medicinal Chemistry LettersDiscovery and optimization of benzenesulfonanilide derivatives as a novel class of 11β-HSD1 inhibitors
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2011, Journal of Steroid Biochemistry and Molecular BiologyCitation Excerpt :For HSDs that belong to the SDR superfamily, non-steroidal based ligands have been based on a number of different pharmacophores. For type 1 11β-HSD, inhibitor series include diverse scaffolds: triazoles (Merck-544) and azabicyclic sulphonamides developed by both Merck and Eli Lilly [76,77]; pentanedioic acid diamides developed by Merck-Serono [78]; pyridinyl arylsulfonamides developed by Pfizer (PF-915275) [79]; (phenylsulfonamido-methyl)-nicotine and (phenylsulfonamido-methyl)-thiazole derivatives [80]; arylsulfonylpiperazines, piperdyl- and cyclo-benzamides developed by Amgen (Amgen 2922) [81–83]; thiazolones developed by Biovitrum (BVT-2733) [84]; 1,5-substituted-1H-tetrazoles developed by the group at Edinburgh [85]; and adamantyl ethanones developed by Ipsen/Sterix [86]. Many of these have nM affinity for the target.
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Present address: ChemoCentryx, Inc., Mountain View, CA 94043, USA.
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Present address: Lundbeck Research USA, Inc., 215 College Road, Paramus, NJ 07652, USA.