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  • Title: Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease.
    Author: Kato A, Nakagome I, Sato K, Yamamoto A, Adachi I, Nash RJ, Fleet GW, Natori Y, Watanabe Y, Imahori T, Yoshimura Y, Takahata H, Hirono S.
    Journal: Org Biomol Chem; 2016 Jan 21; 14(3):1039-48. PubMed ID: 26633162.
    Abstract:
    We report on the synthesis and biological evaluation of a series of α-1-C-alkylated 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives as pharmacological chaperones for Gaucher disease. The parent compound, DAB, did not show inhibition of human β-glucocerebrosidase but showed moderate intestinal α-glucosidase inhibition; in contrast, extension of α-1-C-alkyl chain length gave a series of highly potent and selective inhibitors of the β-glucocerebrosidase. Our design of α-1-C-tridecyl-DAB (5j) produced a potent inhibitor of the β-glucocerebrosidase, with IC50 value of 0.77 μM. A molecular docking study revealed that the α-1-C-tridecyl group has a favorable interaction with the hydrophobic pocket and the sugar analogue part (DAB) interacted with essential hydrogen bonds formed to Asp127, Glu235 and Glu340. Furthermore, α-1-C-tridecyl-DAB (5j) displayed enhancement of activity at an effective concentration 10-times lower than isofagomine. α-1-C-Tridecyl-DAB therefore provides the first example of a pyrrolidine iminosugar as a new class of promising pharmacological chaperones with the potential for treatment of Gaucher disease.
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