RESUMO
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.
Assuntos
Benzotiazóis/síntese química , Benzotiazóis/farmacologia , Fibrose/prevenção & controle , Indóis/síntese química , Indóis/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Animais , Benzotiazóis/farmacocinética , Intoxicação por Tetracloreto de Carbono/tratamento farmacológico , Linhagem Celular , Descoberta de Drogas , Hepatócitos/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Indóis/farmacocinética , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/farmacocinéticaRESUMO
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.