Dual-Action Lipophilic Iminosugar Improves Glycemic Control in Obese Rodents by Reduction of Visceral Glycosphingolipids and Buffering of Carbohydrate Assimilation

作者：Wennekes Tom; Meijer Alfred J; Groen Albert K; Boot Rolf G; Groener Johanna E; van Eijk Marco; Ottenhoff Roelof; Bijl Nora; Ghauharali Karen; Song Hang; O'Shea Tom J; Liu Hanlan; Yew Nelson; Copeland Diane; van den Berg Richard J; van der Marel Gij**ert A; Overkleeft Herman S; Aerts Johannes M^*

来源：Journal of Medicinal Chemistry, 2010, 53(2): 689-698.

DOI：10.1021/jm901281m

The lipophilic iminosugar N-[5-(adamantan-1-ylmethoxy)pentyl]-1-deoxynojirimycin (2, AMP-DNM) potently controls hyperglycemia in obese rodent models of insulin resistance. The reduction of visceral glycosphingolipids by 2 is thought to underlie its beneficial action. It cannot, however, be excluded that concomitant inhibition of intestinal glycosidases and associated buffering of carbohydrate assimilation add to this. To firmly establish the mode of action or 2, we developed a panel of lipophilic iminosugars varying in configuration at C-4/C-5 and N-substitution of the iminosugar. From these we identified the L-ido derivative of 2, L-ido-AMP-DNM (4), as a selective inhibitor of glycosphingolipid synthesis. Compound 4 lowered visceral glycosphingolipids in ob/ob mice and ZDF rats on a par with 2. In contrast to 2, 4 did not inhibit sucrase activity or sucrose assimilation. Treatment with 4 was significantly less effective in reducing blood glucose and HbAlc. We conclude that the combination of reduction of glycosphingolipids in tissue and buffering of carbohydrate assimilation by 2 produces a superior glucose homeostasis.

• 出版日期2010-1-28