Drug Discovery Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., 363 Shiosaki, Hokusei-cho, Inabe-shi, Mie, 511-0406, Japan.
Drug Discovery Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., 363 Shiosaki, Hokusei-cho, Inabe-shi, Mie, 511-0406, Japan.
Eur J Med Chem. 2018 Aug 5;156:269-294. doi: 10.1016/j.ejmech.2018.06.060. Epub 2018 Jun 26.
Glucokinase (GK) is an enzyme that plays an important role as a glucose sensor while maintaining whole body glucose homeostasis. Allosteric activators of GK (GKAs) have the potential to treat type 2 diabetes mellitus. To identify novel GKAs, a series of compounds based on a thiophenyl-pyrrolidine scaffold were designed and synthesized. In this series, compound 38 was found to inhibit glucose excursion in an oral glucose tolerance test (OGTT) in mice. Optimization of 38 using a zwitterion approach led to the identification of the novel GKA 59. GKA 59 exhibited potent blood glucose control in the OGTT test as well as a favorable safety profile. Owing to low pancreatic distribution, compound 59 primarily activates GK in the liver. This characteristic could overcome limitations of other GKAs, such as hypoglycemia, increased plasma triglycerides, and loss of efficacy.
葡萄糖激酶（GK）作为一种葡萄糖传感器，在维持全身葡萄糖稳态方面发挥着重要作用。GK 的别构激活剂（GKAs）有可能用于治疗 2 型糖尿病。为了鉴定新型 GKA，设计并合成了一系列基于噻吩-吡咯烷骨架的化合物。在该系列中，发现化合物 38 可抑制小鼠口服葡萄糖耐量试验（OGTT）中的葡萄糖波动。使用两性离子方法对 38 进行优化，鉴定出新型 GKA 59。GKA 59 在 OGTT 试验中表现出较强的血糖控制作用，且安全性良好。由于胰腺分布较低，化合物 59 主要在肝脏中激活 GK。这一特点可以克服其他 GKA 的一些局限性，如低血糖、血浆甘油三酯升高和疗效丧失。
