Central Research Center, Boryung Pharmaceuticals Co. Ltd., Republic of Korea.
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Republic of Korea.
Bioorg Med Chem Lett. 2019 Aug 15;29(16):2275-2282. doi: 10.1016/j.bmcl.2019.06.027. Epub 2019 Jun 19.
As a potential treatment of type 2 diabetes, a novel PPARγ non-TZD full agonist, compound 18 (BR102375) was identified from the original lead BR101549 by the SAR efforts of the labile metabolite control through bioisosteres approach. In vitro assessments of BR102375 demonstrated its activating potential of PPARγ comparable to Pioglitazone as well as the induction of related gene expressions. Further in vivo evaluation of BR102375 in diabetic rodent models successfully proved its glucose lowering effect as a potential antidiabetic agent, but the anticipated suppression of weight gain was not evident. The X-ray co-crystal analysis of BR102375-PPARγ LBD unexpectedly revealed binding modes totally different from those of BR101549, which was found, instead, closely resembled to those of TZD full agonists.
作为 2 型糖尿病的一种潜在治疗方法，一种新型的 PPARγ 非噻唑烷二酮类全激动剂化合物 18（BR102375）通过生物等排体方法对不稳定代谢物控制的 SAR 研究，从原始先导化合物 BR101549 中被鉴定出来。BR102375 的体外评估表明，它对 PPARγ 的激活潜力与吡格列酮相当，同时也诱导了相关基因的表达。进一步在糖尿病啮齿动物模型中对 BR102375 的体内评估成功证明了它作为潜在抗糖尿病药物的降血糖作用，但预期的体重增加抑制作用并不明显。BR102375-PPARγ LBD 的 X 射线共晶分析出人意料地揭示了与 BR101549 完全不同的结合模式，而后者则与 TZD 全激动剂非常相似。
