Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher diseaseElectronic supplementary information (ESI) available. See DOI: 10.1039/c5ob02223a

• Main Authors: Kato, Atsushi, Nakagome, Izumi, Sato, Kasumi, Yamamoto, Arisa, Adachi, Isao, Nash, Robert J, Fleet, George W. J, Natori, Yoshihiro, Watanabe, Yasuka, Imahori, Tatsushi, Yoshimura, Yuichi, Takahata, Hiroki, Hirono, Shuichi
• Format: Journal Article
• Published: 04.01.2016
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c5ob02223a

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 IC 50 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. α-1- C -Alkylated 1,4-dideoxy-1,4-imino- d -arabinitols (DAB) derivatives as pharmacological chaperones for Gaucher disease.