title: Docking study and biological evaluation of pyrrolidine-based iminosugars as pharmacological chaperones for Gaucher disease.
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.
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. kato@med.u-toyama.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.forename: Izumi
authors.initials: I
authors.lastname: Nakagome
authors.forename: Kasumi
authors.initials: K
authors.lastname: Sato
authors.forename: Arisa
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Isao
authors.initials: I
authors.lastname: Adachi
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Nash
authors.forename: George W J
authors.initials: GW
authors.lastname: Fleet
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Natori
authors.forename: Yasuka
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Imahori
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yoshimura
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahata
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
mesh_terms: D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005776:Gaucher Disease / Q000188:drug therapy* / Q000378:metabolism; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D065089:Glycoside Hydrolase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D050111:Imino Sugars / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D065089:Glycoside Hydrolase Inhibitors; D050111:Imino Sugars; D011759:Pyrrolidines; D005962:Glucosylceramidase; C032519:pyrrolidine