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 R-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.

中文翻译：

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具有前所未有的结合模式的过氧化物酶体增殖物激活受体γ的选择性调节剂。

核过氧化物酶体增殖物激活受体γ在代谢，炎性和神经退行性病变中具有经过充分验证的治疗潜力，但其激活也与明显的不良反应相关，因此需要新的PPARγ调节模式。在这里，我们报道了在正构型PPARγ配体结合位点具有显着效力和独特结合模式的新型PPARγ调节剂化学型的发现和分析。它的R-对映异构体演变为关于PPARγ活化的具有很高的安定比的共聚体。新的PPARγ调节剂对PPARα和PPARδ亚型具有出色的选择性，并且不促进原代人类成纤维细胞的脂肪生成，从而将其与既定的激动剂区分开。