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

• Published in: Journal of medicinal chemistry 2012-12, Vol.55 (23), p.10347-10362
• Main Authors: Kato, Atsushi, Hayashi, Erina, Miyauchi, Saori, Adachi, Isao, Imahori, Tatsushi, Natori, Yoshihiro, Yoshimura, Yuichi, Nash, Robert J., Shimaoka, Hideyuki, Nakagome, Izumi, Koseki, Jun, Hirono, Shuichi, Takahata, Hiroki
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - therapeutic use; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia - drug therapy; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - therapeutic use; Imino Sugars - administration & dosage; Imino Sugars - chemistry; Imino Sugars - pharmacology; Imino Sugars - therapeutic use; Inhibitory Concentration 50; Male; Mice; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm301304e

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.