RESUMEN
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.
Asunto(s)
Benzotiazoles/síntesis química , Benzotiazoles/farmacología , Fibrosis/prevención & control , Indoles/síntesis química , Indoles/farmacología , Receptores Activados del Proliferador del Peroxisoma/agonistas , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Animales , Benzotiazoles/farmacocinética , Intoxicación por Tetracloruro de Carbono/tratamiento farmacológico , Línea Celular , Descubrimiento de Drogas , Hepatocitos/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Indoles/farmacocinética , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Estructura Molecular , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/farmacocinéticaRESUMEN
In the search for new orally active antithrombotic drugs that are metabolically stable, we explored the synthesis of 1-C-(5-thio-D-xylosyl) derivatives, examining radical and nucleophilic methods. Thus synthesized were aryl, benzyl, alkylcarboxymethylenyl, arylsulfonylmethylenyl and alkylaminocarboxymethylenyl C-linked analogues of 5-thio-D-xylopyranosides.