Treatment of hyperglycemia with drugs that block renal glucose reabsorption via inhibition of sodium-dependent glucose cotransporter 2 (SGLT2) is a novel approach to diabetes management. In this study, twenty-seven aryl C-glycosides bearing a C=N/C−N linkage at the glucosyl C6 position were designed, synthesized and evaluated for their inhibitory activity against human SGLT2 (hSGLT2). Compounds with good hSGLT2 inhibition were further investigated to determine their selectivity over hSGLT1. Of these, five representative aryl C-glycosides were chosen for pharmacokinetic analysis. Oxime 2a was determined to have the most promising pharmacokinetic properties and was selected for in vivo glucosuria and plasma glucose level studies, which found it to exhibit comparable efficacy to dapagliflozin (1). Furthermore, 2a was not found to exhibit either significant cytotoxicity (CC₅₀ > 50 μM) or human ether-a-go-go related gene (hERG) inhibition (2% inhibition at 10 μM). Taken together, these efforts culminated in the discovery of oxime 2a as a potential SGLT2 inhibitor.

用可通过抑制钠依赖性葡萄糖共转运蛋白2（SGLT2）阻断肾脏葡萄糖再吸收的药物治疗高血糖症，是治疗糖尿病的一种新方法。在这项研究中，设计，合成和评估了在葡萄糖基C6位置带有C = N / C-N键的27个芳基C-糖苷对人SGLT2（hSGLT2）的抑制活性。进一步研究了具有良好hSGLT2抑制作用的化合物，以确定它们对hSGLT1的选择性。其中，选择五个代表性的芳基C-糖苷进行药代动力学分析。肟2a被确定具有最有希望的药代动力学特性，并被选择用于体内葡萄糖尿和血浆葡萄糖水平的研究，发现它与dapagliflozin（1）表现出可比的功效。此外，未发现2a表现出明显的细胞毒性（CC ₅₀  > 50μM）或人类以太相关基因（hERG）抑制（在10μM时抑制2％）。综上所述，这些努力最终导致了肟2a作为潜在SGLT2抑制剂的发现。