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

J Med Chem. 2012 Dec 13;55(23):10347-62. doi: 10.1021/jm301304e. Epub 2012 Nov 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

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