Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
J Med Chem. 2012 Sep 13;55(17):7828-40. doi: 10.1021/jm300884k. Epub 2012 Aug 28.
Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chemical examination combined with computational modeling resulted in the identification of the clinical candidate 16d (CSG452, tofogliflozin), which is currently under phase III clinical trials.
抑制钠-葡萄糖共转运蛋白 2（SGLT2）已被提议作为治疗 2 型糖尿病的一种新的治疗方法。在我们努力发现新型 SGLT2 抑制剂的过程中，我们首先基于已知抑制剂的叠加生成了一个 3D 药效团模型。使用一系列药效团查询对剑桥结构数据库进行搜索，导致发现了一个 O-螺环缩酮 C-芳基葡糖苷支架。随后的化学研究结合计算建模，确定了临床候选药物 16d（CSG452，托格列净），目前正在进行 III 期临床试验。
