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
The bradykinin (BK) B1 receptor is an attractive target for the treatment of chronic pain and inflammation. Starting from a dual B1 and B2 antagonist, novel antagonists were designed that display low-nanomolar affinity for human B1 receptor and selectivity over B2. Initially, potent imidazoline derivatives were studied, but these compounds suffered from low bioavailability. This issue could be overcome by the use of less basic amino derivatives leading to orally active compounds.