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.

A series of substituted indole-2-carboxylic acid ethyl esters and aza-indole analogs have been prepared using continuous-flow hydrogenation. The identification of some key parameters using a design of experiments (DoE)-based approach allowed efficient optimization of each synthesis. The scale-up study for the multigram preparation of one model indole substrate showed the importance of working at steady state with the H-Cube apparatus. A new useful method for the easy preparation of substituted indoles in various quantities is presented.

No abstract