Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno D'Alcontres, 31, 98166 Messina, Italy.
J Med Chem. 2022 Aug 25;65(16):10848-10881. doi: 10.1021/acs.jmedchem.2c00867. Epub 2022 Aug 4.
Sodium-glucose cotransporter 2 (SGLT-2) inhibitors (gliflozins) represent the most recently approved class of oral antidiabetic drugs. SGLT-2 overexpression in diabetic patients contributes significantly to hyperglycemia and related complications. Therefore, SGLT-2 became a highly interesting therapeutic target, culminating in the approval for clinical use of dapagliflozin and analogues in the past decade. Gliflozins improve glycemic control through a novel insulin-independent mechanism of action and, moreover, exhibit significant cardiorenal protective effects in both diabetic and nondiabetic subjects. Therefore, gliflozins have received increasing attention, prompting extensive structure-activity relationship studies and optimization approaches. The discovery that intestinal SGLT-1 inhibition can provide a novel opportunity to control hyperglycemia, through a multifactorial mechanism, recently encouraged the design of low adsorbable inhibitors selectively directed to the intestinal SGLT-1 subtype as well as of dual SGLT-1/SGLT-2 inhibitors, representing a compelling strategy to identify new antidiabetic drug candidates.
钠-葡萄糖共转运蛋白 2（SGLT-2）抑制剂（格列净类药物）是最近批准的一类口服抗糖尿病药物。糖尿病患者中 SGLT-2 的过度表达对高血糖及其相关并发症有重要贡献。因此，SGLT-2 成为一个极具吸引力的治疗靶点，最终在过去十年中批准了达格列净及其类似物的临床应用。格列净类药物通过一种新颖的胰岛素非依赖性作用机制改善血糖控制，而且在糖尿病和非糖尿病患者中均具有显著的心脏和肾脏保护作用。因此，格列净类药物受到了越来越多的关注，促使人们进行了广泛的构效关系研究和优化方法。最近发现，通过多因素作用机制抑制肠道 SGLT-1 可以为控制高血糖提供新的机会，这促使人们设计了对肠道 SGLT-1 亚型具有低吸附性的选择性抑制剂，以及 SGLT-1/SGLT-2 双重抑制剂，这代表了一种很有前途的策略，可以鉴定新的抗糖尿病药物候选物。
