RESUMEN
A high-throughput screen against Inventiva's compound library using a Gal4/RORγ-LBD luciferase reporter gene assay led to the discovery of a new series of quinoline sulphonamides as RORγ inhibitors, eventually giving rise to a lead compound having an interesting in vivo profile after oral administration. This lead was evaluated in a target engagement model in mouse, where it reduced IL-17 cytokine production after immune challenge. It also proved to be active in a multiple sclerosis model (EAE) where it reduced the disease score. The synthesis, structure activity relationship (SAR) and biological activity of these derivatives is described herein.
Asunto(s)
Agonismo Inverso de Drogas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/química , Quinolinas/química , Animales , Modelos Animales de Enfermedad , Humanos , RatonesRESUMEN
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
Protein kinase Cθ (PKCθ) regulates a key step in the activation of T cells. On the basis of its mechanism of action, inhibition of this kinase is hypothesized to serve as an effective therapy for autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Herein, the discovery of a small molecule PKCθ inhibitor is described, starting from a fragment hit 1 and advancing to compound 41 through the use of structure-based drug design. Compound 41 demonstrates excellent in vitro activity, good oral pharmacokinetics, and efficacy in both an acute in vivo mechanistic model and a chronic in vivo disease model but suffers from tolerability issues upon chronic dosing.
Asunto(s)
Isoenzimas/antagonistas & inhibidores , Isoenzimas/química , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Animales , Área Bajo la Curva , Artritis Experimental/tratamiento farmacológico , Disponibilidad Biológica , Células Cultivadas , Cromatografía Liquida , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Descubrimiento de Drogas , Femenino , Humanos , Isoenzimas/metabolismo , Espectrometría de Masas , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Modelos Moleculares , Estructura Molecular , Unión Proteica , Proteína Quinasa C/metabolismo , Proteína Quinasa C-theta , Inhibidores de Proteínas Quinasas/farmacocinética , Estructura Terciaria de Proteína , Ratas , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacocinética , Bibliotecas de Moléculas Pequeñas/farmacología , Linfocitos T/efectos de los fármacosRESUMEN
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.