Senior Research Fellow, Metabolic Diseases Chemistry, Research and Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, USA.
Expert Opin Ther Pat. 2009 Nov;19(11):1485-99. doi: 10.1517/13543770903337828.
A critical factor for maintenance of glucose balance is the renal recovery of glucose from the glomerular filtrate mediated primarily by sodium glucose co-transporter 2 (SGLT2). This capacity can be modulated by SGLT2 inhibitors thereby providing a unique insulin independent method of treatment of diabetes.
OBJECTIVE/METHOD: A discussion of the evolution of SGLT inhibitors as inferred from patents published from 2005 to 2009 is prefaced by a brief review of the role of SGLT in glucose transport and the clinical findings illustrating the therapeutic potential of SGLT inhibitors as anti-diabetic agents. These compounds comprise O, C and N-glycosides generated by attachment of an appropriate lipophilic aglycone component to a suitable glucose analogue.
The realization that the in vivo potency of O-glucosides was markedly less than that of C-glucosides necessitated a shift in medicinal chemistry focus of the pharmaceutical companies pursuing SGLT2 inhibitors. Particular emphasis is placed on the strategy that each used to circumvent the constraints imposed by prior art while utilizing a common pharmacophore. The role of SGLT2 inhibitors for treatment of diabetes will be established by the outcome of the five compounds in advanced clinical trials.
维持血糖平衡的一个关键因素是肾脏通过主要由钠-葡萄糖协同转运蛋白 2（SGLT2）介导从肾小球滤过液中回收葡萄糖。这种能力可以通过 SGLT2 抑制剂进行调节，从而为糖尿病的治疗提供了一种独特的、不依赖胰岛素的方法。
目的/方法：从 2005 年至 2009 年发表的专利中推断出 SGLT 抑制剂的演变，并简要回顾 SGLT 在葡萄糖转运中的作用以及临床研究结果，这些结果说明了 SGLT 抑制剂作为抗糖尿病药物的治疗潜力。这些化合物包括通过将合适的亲脂性非糖部分连接到合适的葡萄糖类似物上而产生的 O、C 和 N-糖苷。
体内 O-糖苷的效力明显低于 C-糖苷，这一认识促使从事 SGLT2 抑制剂研究的制药公司将药物化学研究重点转移。特别强调的是，每家公司都利用共同的药效基团来规避现有技术的限制，同时利用共同的药效基团。SGLT2 抑制剂在糖尿病治疗中的作用将通过正在进行的五项临床试验的结果来确定。
