School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China; Key Laboratory of New Drug Discovery and Evaluation, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, PR China.
Bioorg Chem. 2020 Aug;101:103963. doi: 10.1016/j.bioorg.2020.103963. Epub 2020 May 25.
Dual PPARα/δ agonists have been considered as potential therapeutics for the treatment of type 2 diabetes mellitus. After comprehensive structure-activity relationship study based on GFT505, a novel dual PPARα/δ agonist compound 6 was identified with highly activities on PPARα/δ and higher selectivity against PPARγ than that of GFT505. The modeling study revealed that compound 6 binds well to the binding pockets of PPARα and PPARδ, which formed multiple hydrogen bonds with key residues related to the activation of PPARα and PPARδ. Moreover, oral glucose tolerance test exhibited that compound 6 exerts dose-dependent anti-diabetic effects in ob/ob mice and reveals similar potency to that of GFT505, the most advanced candidate in this field. These findings suggested that compound 6 is a promising candidate for further researches, and the extended chemical space might help us to explore better PPARα/δ agonist.
双重 PPARα/δ 激动剂已被认为是治疗 2 型糖尿病的潜在治疗药物。在基于 GFT505 的全面结构-活性关系研究之后，发现了一种新型双重 PPARα/δ 激动剂化合物 6，其对 PPARα/δ 的活性较高，对 PPARγ 的选择性高于 GFT505。建模研究表明，化合物 6 与 PPARα 和 PPARδ 的结合口袋结合良好，与与 PPARα 和 PPARδ 的激活相关的关键残基形成了多个氢键。此外，口服葡萄糖耐量试验表明，化合物 6 在 ob/ob 小鼠中具有剂量依赖性的抗糖尿病作用，其效力与该领域最先进的候选药物 GFT505 相似。这些发现表明，化合物 6 是进一步研究的有前途的候选药物，扩展的化学空间可能有助于我们探索更好的 PPARα/δ 激动剂。
