Here, we describe the identification and synthesis of novel indole sulfonamide derivatives that activate the three peroxisome proliferator activated receptor (PPAR) isoforms. Starting with a PPARα activator, compound 4, identified during a high throughput screening (HTS) of our proprietary screening library, a systematic optimization led to the discovery of lanifibranor (IVA337) 5, a moderately potent and well balanced pan PPAR agonist with an excellent safety profile. In vitro and in vivo, compound 5 demonstrated strong activity in models that are relevant to nonalcoholic steatohepatitis (NASH) pathophysiology suggesting therapeutic potential for NASH patients.

中文翻译：

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设计，合成和评估新型系列的吲哚磺酰胺过氧化物酶体增殖物激活受体（PPAR）α/γ/δ三重激活剂：Lanifibranor的发现，一种新的抗纤维化临床候选药物

在这里，我们描述了激活三种过氧化物酶体增殖物激活受体（PPAR）同工型的新型吲哚磺酰胺衍生物的鉴定和合成。从在我们专有筛选库的高通量筛选（HTS）中鉴定的PPARα激活剂化合物4开始，系统优化导致发现了lanifibranor（IVA337）5，这是一种中等强度且平衡良好的泛PPAR激动剂，具有出色的安全档案。在体外和体内，化合物5在与非酒精性脂肪性肝炎（NASH）病理生理相关的模型中显示出强大的活性，这表明NASH患者具有治疗潜力。