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
We previously demonstrated that selective inhibition of protein kinase Cθ (PKCθ) with triazinone 1 resulted in dose-dependent reduction of paw swelling in a mouse model of arthritis.1,2 However, a high concentration was required for efficacy, thus providing only a minimal safety window. Herein we describe a strategy to deliver safer compounds based on the hypothesis that optimization of potency in concert with good oral pharmacokinetic (PK) properties would enable in vivo efficacy at reduced exposures, resulting in an improved safety window. Ultimately, transformation of 1 yielded analogues that demonstrated excellent potency and PK properties and fully inhibited IL-2 production in an acute model. In spite of good exposure, twice-a-day treatment with 17l in the glucose-6-phosphate isomerase chronic in vivo mouse model of arthritis yielded only moderate efficacy. On the basis of the exposure achieved, we conclude that PKCθ inhibition alone is insufficient for complete efficacy in this rodent arthritis model.
Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/metabolismo , Artrite Experimental/metabolismo , Cristalografia por Raios X , Modelos Animais de Doenças , Humanos , Interleucina-2/metabolismo , Isoenzimas/química , Isoenzimas/metabolismo , Masculino , Camundongos , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Proteína Quinase C/química , Proteína Quinase C/metabolismo , Proteína Quinase C-theta , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Resultado do TratamentoRESUMO
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
Modification of a 2-iminobenzimidazole series derived from an HTS hit resulted in compounds with improved in-vitro species selectivity. Incorporation of an 8-quinoline amide and conformational rigidification of an aliphatic tether furnished potent compounds suitable for further lead optimization.