RESUMEN
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
Tau-tubulin kinase 1 (TTBK1) is a dual-specificity (serine/threonine and tyrosine) kinase belonging to the casein kinase 1 superfamily. TTBK1 is a neuron-specific kinase that regulates tau phosphorylation. Hyperphosphorylation of tau is implicated in the pathogenesis of Alzheimer's disease. Two kinase-domain constructs of TTBK1 were expressed in a baculovirus-infected insect-cell system and purified. The purified TTBK1 kinase-domain proteins were crystallized using the hanging-drop vapor-diffusion method. X-ray diffraction data were collected and the structure of TTBK1 was determined by molecular replacement both as an apo structure and in complex with a kinase inhibitor.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/química , Animales , Baculoviridae/genética , Cristalización , Cristalografía por Rayos X , Electroforesis en Gel de Poliacrilamida , Humanos , Espectroscopía de Resonancia Magnética , Conformación Proteica , Células Sf9 , Especificidad por SustratoRESUMEN
A new class of lymphocyte function-associated antigen-1 (LFA-1) antagonists is described. Elaboration of the 2,3-dihydro-1H-pyrrolizin-5(7aH)-one scaffold resulted in the synthesis of potent inhibitors of the LFA-1/ICAM-1 interaction. Along with the in vitro activity, we present the X-ray crystal structure of the complex of compound 9b, in a novel binding mode to the I-domain of LFA-1.
Asunto(s)
Química Farmacéutica/métodos , Antígeno-1 Asociado a Función de Linfocito/química , Pirroles/química , Cristalografía por Rayos X , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Estereoisomerismo , Temperatura , Rayos XRESUMEN
LFA-1 (leukocyte function-associated antigen-1), is a member of the beta(2)-integrin family and is expressed on all leukocytes. The LFA-1/ICAM interaction promotes tight adhesion between activated leukocytes and the endothelium, as well as between T cells and antigen-presenting cells. Evidence from both animal models and clinical trials provides support for LFA-1 as a target in several different inflammatory diseases. This paper describes the de novo design, synthesis and in vitro activity of LFA-1 antagonists based on a bicyclic[5.5]hydantoin scaffold.
