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
| Autor: | Yuichi Yoshimura, Yoshihiro Natori, Erina Hayashi, Atsushi Kato, Hiroki Takahata, Saori Miyauchi, Robert J. Nash, Jun Koseki, Izumi Nakagome, Hideyuki Shimaoka, Isao Adachi, Tatsushi Imahori, Shuichi Hirono |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Stereochemistry Iminosugar Administration Oral Sucrase Inhibitory Concentration 50 Mice Drug Discovery medicine Animals Humans Hypoglycemic Agents Glycoside Hydrolase Inhibitors Enzyme Inhibitors chemistry.chemical_classification Chemistry Negishi coupling Miglitol Oligosaccharide Imino Sugars Postprandial Hyperglycemia Spectrometry Mass Matrix-Assisted Laser Desorption-Ionization Molecular Medicine Maltase Isomaltase medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 55:10347-10362 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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