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
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.
Asunto(s)
Amidas/farmacología , Bencimidazoles/farmacología , Quinolinas/farmacología , Receptores CXCR3/antagonistas & inhibidores , Amidas/química , Animales , Bencimidazoles/síntesis química , Sitios de Unión , Células CHO/efectos de los fármacos , Cricetinae , Cricetulus , Humanos , Modelos Químicos , Quinolinas/química , Ensayo de Unión Radioligante , Receptores CXCR3/metabolismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antiinflamatorios/farmacología , Artritis Experimental/tratamiento farmacológico , Isoenzimas/antagonistas & inhibidores , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Animales , Antiinflamatorios/química , Antiinflamatorios/metabolismo , Artritis Experimental/metabolismo , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Humanos , Interleucina-2/metabolismo , Isoenzimas/química , Isoenzimas/metabolismo , Masculino , Ratones , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Proteína Quinasa C/química , Proteína Quinasa C/metabolismo , Proteína Quinasa C-theta , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Estructura Terciaria de Proteína , Resultado del TratamientoRESUMEN
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.