?-1-C-Butyl-1,4-dideoxy-1,4-imino-l-arabinitolas a Second-Generation Iminosugar-Based Oral ?-GlucosidaseInhibitor for Improving Postprandial Hyperglycemia.

We report on the synthesis and the biological evaluationof a series of ?-1-C-alkylated 1,4-dideoxy-1,4-imino-l-arabinitol (LAB) derivatives. The asymmetric synthesis ofthe derivatives was achieved by asymmetric allylic alkylation, ring-closingmetathesis, and Negishi cross-coupling as key reactions. ?-1-C-Butyl-LAB is a potent inhibitor of intestinal maltase,isomaltase, and sucrase, with IC50values of 0.13, 4.7,and 0.032 ?M, respectively. Matrix-assisted laser desorptionionization time-of-flight mass spectrometric analysis revealed thatthis compound differs from miglitol in that it does not influenceoligosaccharide processing and the maturation of glycoproteins. Amolecular docking study of maltase-glucoamylase suggested that theinteraction modes and the orientations of ?-1-C-butyl-LAB and miglitol are clearly different. Furthermore, ?-1-C-butyl-LAB strongly suppressed postprandial hyperglycemiaat an early phase, similar to miglitol in vivo. It is noteworthy thatthe effective dose was about 10-fold lower than that for miglitol.?-1-C-Butyl-LAB therefore represents a newclass of promising compounds that can improve postprandial hyperglycemia. [ABSTRACT FROM AUTHOR]