alpha-1-C-Butyl-1,4-dideoxy-1,4-imino-L-arabinitol as a Second-Generation Iminosugar-Based Oral alpha-Glucosidase Inhibitor for Improving Postprandial Hyperglycemia

作者：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

来源：Journal of Medicinal Chemistry, 2012, 55(23): 10347-10362.

DOI：10.1021/jm301304e

We report on the synthesis and the biological evaluation of a series of alpha-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. alpha-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 mu M, 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 alpha-1-C-butyl-LAB and miglitol are clearly different. Furthermore, a-l-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. alpha-1-C-Butyl-LAB therefore represents a new class of promising compounds that can improve postprandial hyperglycemia.

• 出版日期2012-12-13