Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
Branch for Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Theodor-Stern-Kai 7, 60596 Frankfurt, Germany.
J Med Chem. 2020 May 14;63(9):4555-4561. doi: 10.1021/acs.jmedchem.9b01786. Epub 2020 Apr 20.
The nuclear peroxisome proliferator-activated receptor γ has well-validated therapeutic potential in metabolic, inflammatory, and neurodegenerative pathologies, but its activation is also associated with marked adverse effects and novel modes of PPARγ modulation are required. Here, we report the discovery and profiling of a new PPARγ modulator chemotype endowed with remarkable potency and a distinct binding mode in the orthosteric PPARγ ligand-binding site. Its -enantiomer evolved as a eutomer regarding PPARγ activation with a high eudysmic ratio. The new PPARγ modulator revealed outstanding selectivity over the PPARα and PPARδ subtypes and did not promote adipogenesis in primary human fibroblasts, discriminating it from established agonists.
核过氧化物酶体增殖物激活受体 γ 在代谢、炎症和神经退行性病变方面具有良好的治疗潜力，但它的激活也与明显的不良反应有关，需要新的 PPARγ 调节模式。在这里，我们报告了一种新的 PPARγ 调节剂化学类型的发现和分析，该化学类型在正位 PPARγ 配体结合位点具有显著的效力和独特的结合模式。其 - 对映异构体在 PPARγ 激活方面表现出高 eudysmic 比值的优势异构体。新型 PPARγ 调节剂对 PPARα 和 PPARδ 亚型表现出优异的选择性，并且不会促进原代人成纤维细胞的脂肪生成，使其与已建立的激动剂区分开来。
