RESUMEN
SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound 1 (BMS-986251) led to tricyclic-carbocyclic analogues represented by 3-7 and culminated in the identification of 3d (BMS-986313), with structural differences distinct from 1. The X-ray co-crystal structure of 3d with the ligand binding domain of RORγt revealed several key interactions, which are different from 1. The in vitro and in vivo PK profiles of 3d are described. In addition, we demonstrate robust efficacy of 3d in two preclinical models of psoriasis-the IMQ-induced skin lesion model and the IL-23-induced acanthosis model. The efficacy seen with 3d in these models is comparable to the results observed with 1.
Asunto(s)
Amidas/uso terapéutico , Hidrocarburos Cíclicos/uso terapéutico , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/antagonistas & inhibidores , Psoriasis/tratamiento farmacológico , Amidas/química , Amidas/farmacocinética , Animales , Agonismo Inverso de Drogas , Femenino , Humanos , Hidrocarburos Cíclicos/química , Hidrocarburos Cíclicos/farmacocinética , Interleucina-23 , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Estructura Molecular , Psoriasis/inducido químicamente , Ratas , Relación Estructura-ActividadRESUMEN
RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule 32 with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.
Asunto(s)
Diseño de Fármacos , Agonismo Inverso de Drogas , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/agonistas , Pirrolidinas/farmacología , Animales , Humanos , Células Jurkat , Ratones , Modelos Moleculares , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/química , Conformación Proteica , Pirrolidinas/química , Pirrolidinas/farmacocinética , Relación Estructura-Actividad , Distribución TisularRESUMEN
Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, is a member of the Tec family of kinases and is essential for B cell receptor (BCR) mediated signaling. BTK also plays a critical role in the downstream signaling pathways for the Fcγ receptor in monocytes, the Fcε receptor in granulocytes, and the RANK receptor in osteoclasts. As a result, pharmacological inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as rheumatoid arthritis and lupus. This article will outline the evolution of our strategy to identify a covalent, irreversible inhibitor of BTK that has the intrinsic potency, selectivity, and pharmacokinetic properties necessary to provide a rapid rate of inactivation systemically following a very low dose. With excellent in vivo efficacy and a very desirable tolerability profile, 5a (branebrutinib, BMS-986195) has advanced into clinical studies.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Descubrimiento de Drogas , Indoles/farmacología , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Animales , Artritis Reumatoide/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Humanos , Indoles/farmacocinética , Indoles/uso terapéutico , Concentración 50 Inhibidora , Lupus Eritematoso Sistémico/tratamiento farmacológico , Macaca fascicularis , Ratones , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Relación Estructura-Actividad , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Células CACO-2/efectos de los fármacos , Células CACO-2/inmunología , Perros , Canal de Potasio ERG1/metabolismo , Inhibidores Enzimáticos/química , Femenino , Humanos , Enfermedades del Sistema Inmune/tratamiento farmacológico , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Lectinas Tipo C/metabolismo , Masculino , Ratones Endogámicos BALB C , Pirazoles/química , Pirazoles/metabolismo , Pirazoles/farmacología , ConejosRESUMEN
Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure-activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, 14f (BMS-986142) was advanced into clinical studies.
Asunto(s)
Carbazoles/química , Carbazoles/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa , Animales , Carbazoles/farmacocinética , Cristalografía por Rayos X , Femenino , Humanos , Isomerismo , Macaca fascicularis , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Tirosina Quinasas/metabolismo , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Relación Estructura-ActividadRESUMEN
Bruton's tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure-activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]-9H-carbazole-1-carboxamide 6 (BMS-935177) was selected to advance into clinical development.