RESUMEN
2-aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 approximately 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFalpha production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Pirimidinas/síntesis química , Tiazoles/síntesis química , Familia-src Quinasas/antagonistas & inhibidores , Administración Oral , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Enfermedad Crónica , Dasatinib , Femenino , Humanos , Técnicas In Vitro , Inflamación/sangre , Inflamación/inducido químicamente , Interleucina-2/antagonistas & inhibidores , Lipopolisacáridos , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Modelos Moleculares , Unión Proteica , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Ratas Endogámicas Lew , Relación Estructura-Actividad , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Tiazoles/química , Tiazoles/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
A novel series of 2-amino-5-carboxamidothiazoles were identified as inhibitors of Lck. Structure-activity studies demonstrate the structural requirements for potent Lck activity. Cyclopropylamide 11d is a potent Lck inhibitor having sub-micromolar activity in a PBL proliferation assay.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Tiazoles/síntesis química , Tiazoles/farmacología , Secuencia de Aminoácidos , Sitios de Unión , Diseño de Fármacos , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/química , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy.
Asunto(s)
Amidas/farmacología , Antiinflamatorios/farmacología , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Tiazoles/farmacología , Familia-src Quinasas/antagonistas & inhibidores , Administración Oral , Amidas/síntesis química , Amidas/farmacocinética , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Artritis Experimental/terapia , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Masculino , Modelos Moleculares , Estructura Molecular , Ratas , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacocinéticaRESUMEN
We have identified a novel series of 1,5-imidazoquinoxalines as inhibitors of Lck with excellent potency (IC50s<5 nM) as well as good cellular activity against T-cell proliferation (IC50s<1 microM). Structure-activity studies demonstrate the requirement for the core heterocycle in addition to an optimal 2,6-disubstituted aniline group.