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: Atsushi Kato, Erina Hayashi, Saori Miyauchi, Isao Adachi, Tatsushi Imahori, Yoshihiro Natori, Yuichi Yoshimura, Robert J Nash, Hideyuki Shimaoka, Izumi Nakagome, Jun Koseki, Shuichi Hirono, Hiroki Takahata
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 23 Pg. 10347-62 (Dec 13 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 23106358 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Glycoside Hydrolase Inhibitors
• Hypoglycemic Agents
• Imino Sugars
• alpha-1-C-butyl-1,4-dideoxy-1,4-imino-L-arabinitol

Topics

• Administration, Oral
• Animals
• Enzyme Inhibitors (administration & dosage, chemistry, therapeutic use)
• Glycoside Hydrolase Inhibitors
• Humans
• Hyperglycemia (drug therapy)
• Hypoglycemic Agents (administration & dosage, chemistry, therapeutic use)
• Imino Sugars (administration & dosage, chemistry, pharmacology, therapeutic use)
• Inhibitory Concentration 50
• Male
• Mice
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization