RESUMEN
Sphingosine-1-phosphate (S1P) binds to a family of sphingosine-1-phosphate G-protein-coupled receptors (S1P1-5). The interaction of S1P with these S1P receptors has a fundamental role in many physiological processes in the vascular and immune systems. Agonist-induced functional antagonism of S1P1 has been shown to result in lymphopenia. As a result, agonists of this type hold promise as therapeutics for autoimmune disorders. The previously disclosed differentiated S1P1 modulator BMS-986104 (1) exhibited improved preclinical cardiovascular and pulmonary safety profiles as compared to earlier full agonists of S1P1; however, it demonstrated a long pharmacokinetic half-life (T1/2 18 days) in the clinic and limited formation of the desired active phosphate metabolite. Optimization of this series through incorporation of olefins, ethers, thioethers, and glycols into the alkyl side chain afforded an opportunity to reduce the projected human T1/2 and improve the formation of the active phosphate metabolite while maintaining efficacy as well as the improved safety profile. These efforts led to the discovery of 12 and 24, each of which are highly potent, biased agonists of S1P1. These compounds not only exhibited shorter in vivo T1/2 in multiple species but are also projected to have significantly shorter T1/2 values in humans when compared to our first clinical candidate. In models of arthritis, treatment with 12 and 24 demonstrated robust efficacy.
Asunto(s)
Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/farmacología , Proproteína Convertasas/efectos de los fármacos , Serina Endopeptidasas/efectos de los fármacos , Animales , Artritis Experimental/tratamiento farmacológico , Enfermedades Autoinmunes/tratamiento farmacológico , Biotransformación , Compuestos Bicíclicos con Puentes/efectos adversos , Líquido del Lavado Bronquioalveolar , Quimiotaxis de Leucocito/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Enfermedades Pulmonares/inducido químicamente , Enfermedades Pulmonares/patología , Masculino , Miocitos Cardíacos/efectos de los fármacos , Fosforilación , Ratas , Ratas Endogámicas Lew , Relación Estructura-ActividadRESUMEN
A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads.
Asunto(s)
Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Sitios de Unión , Dominio Catalítico , Línea Celular , Supervivencia Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Janus Quinasa 3/metabolismo , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
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
A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.
Asunto(s)
Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 3/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Piridazinas/química , Pirroles/química , Animales , Sitios de Unión , Dominio Catalítico , Línea Celular , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Inflamación/prevención & control , Concentración 50 Inhibidora , Janus Quinasa 1/metabolismo , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Janus Quinasa 3/metabolismo , Ratones , Ratones Endogámicos BALB C , Conformación Molecular , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Piridazinas/síntesis química , Piridazinas/farmacocinética , Pirroles/síntesis química , Pirroles/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , TYK2 Quinasa/antagonistas & inhibidores , TYK2 Quinasa/metabolismoRESUMEN
As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.
Asunto(s)
Aminas/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Aminas/metabolismo , Aminas/uso terapéutico , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , Sitios de Unión , Fosfatidilinositol 3-Quinasa Clase I , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Piperazina , Piperazinas/química , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Relación Estructura-Actividad , Triazinas/químicaRESUMEN
Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.
Asunto(s)
Aminas/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Triazinas/química , Aminas/metabolismo , Aminas/uso terapéutico , Animales , Artritis/tratamiento farmacológico , Artritis/metabolismo , Artritis/patología , Sitios de Unión , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Concentración 50 Inhibidora , Ratones , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Unión Proteica , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Estructura Terciaria de Proteína , 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.
Asunto(s)
Antirreumáticos/química , Carbazoles/química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Quinazolinonas/química , Administración Oral , Agammaglobulinemia Tirosina Quinasa , Animales , Antirreumáticos/síntesis química , Antirreumáticos/farmacocinética , Antirreumáticos/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/patología , Disponibilidad Biológica , Carbazoles/síntesis química , Carbazoles/farmacocinética , Carbazoles/farmacología , Línea Celular , Cristalografía por Rayos X , Perros , Humanos , Macaca fascicularis , Ratones , Microsomas Hepáticos/metabolismo , Permeabilidad , Proteínas Tirosina Quinasas/química , Quinazolinonas/síntesis química , Quinazolinonas/farmacocinética , Quinazolinonas/farmacología , Relación Estructura-ActividadRESUMEN
The synthesis and structure-activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Lisofosfolípidos/agonistas , Esfingosina/análogos & derivados , Relación Estructura-Actividad , Administración Oral , Animales , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Humanos , Isoxazoles/química , Isoxazoles/farmacología , Recuento de Linfocitos , Masculino , Ratas Endogámicas Lew , Receptores de Lisoesfingolípidos/agonistas , Esfingosina/agonistasRESUMEN
An empirical approach to improve the microsomal stability and CYP inhibition profile of lead compounds 1a and 1b led to the identification of 5 (BMS-341) as a dissociated glucocorticoid receptor modulator. Compound 5 showed significant improvements in pharmacokinetic properties and, unlike compounds 1a-b, displayed a linear, dose-dependent pharmacokinetic profile in rats. When tested in a chronic model of adjuvant-induced arthritis in rat, the ED50 of 5 (0.9 mg/kg) was superior to that of both 1a and 1b (8 and 17 mg/kg, respectively).