RESUMO
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.
Assuntos
Agonismo Inverso de Drogas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/química , Quinolinas/química , Animais , Modelos Animais de Doenças , Humanos , CamundongosRESUMO
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
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.
Assuntos
Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Área Sob a Curva , Artrite Experimental/tratamento farmacológico , Disponibilidade Biológica , Células Cultivadas , Cromatografia Líquida , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Desenho de Fármacos , Descoberta de Drogas , Feminino , Humanos , Isoenzimas/metabolismo , Espectrometria de Massas , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos DBA , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Proteína Quinase C/metabolismo , Proteína Quinase C-theta , Inibidores de Proteínas Quinases/farmacocinética , Estrutura Terciária de Proteína , Ratos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/farmacologia , Linfócitos T/efeitos dos fármacosRESUMO
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.