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 Feb 15;29(4):631-637. doi: 10.1016/j.bmcl.2018.12.043. Epub 2018 Dec 19.
The new class of PPARgamma non-TZD agonist originally derived from the backbone of anti-hypertensive Fimasartan, BR101549, was identified as a potential lead for anti-diabetic drug development. The X-ray crystallography of BR101549 with PPARgamma ligand binding domain (LBD) revealed unique binding characteristics versus traditional TZD full agonists. The lead candidate, BR101549, has been found activating PPARgamma to the level of Pioglitazone in vitro and indeed has demonstrated its effects on blood glucose control in mouse proof-of-concept evaluation. The attempts to improve its metabolic stability profile through follow-up SAR including deuterium incorporation have been also described.
新型 PPARγ 非噻唑烷二酮类激动剂最初源于抗高血压药物 Fimasartan 的骨架，即 BR101549，被鉴定为抗糖尿病药物开发的潜在先导化合物。BR101549 与 PPARγ 配体结合域 (LBD) 的 X 射线晶体学揭示了与传统 TZD 完全激动剂相比的独特结合特征。先导候选化合物 BR101549 在体外已被发现能激活 PPARγ 的作用，达到吡格列酮的水平，并且在小鼠概念验证评估中确实显示了其对血糖控制的效果。还描述了通过后续 SAR 研究（包括氘掺入）来提高其代谢稳定性的尝试。
