title: α-1-C-butyl-1,4-dideoxy-1,4-imino-l-arabinitol as a second-generation iminosugar-based oral α-glucosidase inhibitor for improving postprandial hyperglycemia.
abstract: We report on the synthesis and the biological evaluation of a series of α-1-C-alkylated 1,4-dideoxy-1,4-imino-l-arabinitol (LAB) derivatives. The asymmetric synthesis of the derivatives was achieved by asymmetric allylic alkylation, ring-closing metathesis, and Negishi cross-coupling as key reactions. α-1-C-Butyl-LAB is a potent inhibitor of intestinal maltase, isomaltase, and sucrase, with IC50 values of 0.13, 4.7, and 0.032 μM, respectively. Matrix-assisted laser desorption ionization time-of-flight mass spectrometric analysis revealed that this compound differs from miglitol in that it does not influence oligosaccharide processing and the maturation of glycoproteins. A molecular docking study of maltase-glucoamylase suggested that the interaction modes and the orientations of α-1-C-butyl-LAB and miglitol are clearly different. Furthermore, α-1-C-butyl-LAB strongly suppressed postprandial hyperglycemia at an early phase, similar to miglitol in vivo. It is noteworthy that the effective dose was about 10-fold lower than that for miglitol. α-1-C-Butyl-LAB therefore represents a new class of promising compounds that can improve postprandial hyperglycemia.
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama 930-0194, Japan. kato@med.u-toyama.ac.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.forename: Erina
authors.initials: E
authors.lastname: Hayashi
authors.forename: Saori
authors.initials: S
authors.lastname: Miyauchi
authors.forename: Isao
authors.initials: I
authors.lastname: Adachi
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Imahori
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Natori
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yoshimura
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Nash
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Shimaoka
authors.forename: Izumi
authors.initials: I
authors.lastname: Nakagome
authors.forename: Jun
authors.initials: J
authors.lastname: Koseki
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takahata
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D065089:Glycoside Hydrolase Inhibitors; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D050111:Imino Sugars / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D004791:Enzyme Inhibitors; D065089:Glycoside Hydrolase Inhibitors; D007004:Hypoglycemic Agents; D050111:Imino Sugars; C578438:alpha-1-C-butyl-1,4-dideoxy-1,4-imino-L-arabinitol