RESUMEN
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
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).
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacología , Receptores de Glucocorticoides/metabolismo , Tiadiazoles/farmacología , Animales , Sangre/efectos de los fármacos , Sangre/metabolismo , Técnicas de Química Sintética , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A/química , Inhibidores del Citocromo P-450 CYP3A/farmacología , Inhibidores Enzimáticos del Citocromo P-450/química , Inhibidores Enzimáticos del Citocromo P-450/farmacocinética , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Estabilidad de Medicamentos , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Humanos , Masculino , Ratas Endogámicas Lew , Receptores de Glucocorticoides/agonistas , Relación Estructura-Actividad , Tiadiazoles/química , Tiadiazoles/farmacocinética , Factor de Transcripción AP-1/metabolismoRESUMEN
Tristetraprolin (TTP) is a widely expressed, zinc finger-containing protein that has been implicated in the regulation of TNFalpha production in mice. Stimulus-dependent cytoplasmic translocation of TTP has been demonstrated in several cells. In this report we used the yeast two-hybrid screen to identify proteins able to interact with full length, human TTP. One of the isolated TTP-interacting clones encoded the FG repeat region of the nuclear pore protein Nup214. Full length Nup214 co-precipitated with TTP from resting and LPS-stimulated THP-1 cells, indicating that this interaction occurred in intact cells. The ability of TTP to associate with Nup214 was dependent on two intact zinc fingers within TTP. In contrast to wild type TTP that localized primarily in the cytosol, a mutant unable to associate with Nup214 localized throughout the cell, suggesting that the interaction with Nup214 regulates TTP localization.