RESUMEN
A series of novel acylsulfonamide, acylsulfamide, and sulfonylurea bioisosteres of carboxylic acids were prepared as CXCR2 antagonists. Structure-activity relationships are reported for these series. One potent orally bioavailable inhibitor had excellent PK properties and was active in a lung injury model in hyperoxia-exposed newborn rats.
Asunto(s)
Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Pulmón/efectos de los fármacos , Receptores de Interleucina-8B/antagonistas & inhibidores , Sulfonamidas/química , Ácidos Sulfónicos/química , Compuestos de Sulfonilurea/química , Administración Oral , Animales , Animales Recién Nacidos , Disponibilidad Biológica , Lavado Broncoalveolar , Ácidos Carboxílicos/farmacocinética , Quimiotaxis/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/metabolismo , Humanos , Hiperoxia , Pulmón/metabolismo , Lesión Pulmonar , Estructura Molecular , Neutrófilos/metabolismo , Conejos , Ratas , Relación Estructura-ActividadRESUMEN
A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). The fully optimized compound, 4-(4-ethyl-phenyl)-3-(2-methyl-3H-imidazol-4-yl)-2-quinolone-6-carbonitrile 21b, has an IC(50) of 2.5 nM in an in vitro assay and 5.0 nM in a bone marrow-derived macrophage cellular assay. Inhibition of FMS signaling in vivo was also demonstrated in a mouse pharmacodynamic model.
Asunto(s)
Macrófagos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Quinolonas/síntesis química , Quinolonas/farmacología , Receptor de Factor Estimulante de Colonias de Macrófagos/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Proliferación Celular/efectos de los fármacos , Polarización de Fluorescencia , Genes fos/genética , Factor Estimulante de Colonias de Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Quinolonas/farmacocinética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Receptor de Factor Estimulante de Colonias de Macrófagos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Bazo/metabolismo , Relación Estructura-ActividadRESUMEN
There is increasing evidence that tumor-associated macrophages promote the malignancy of some cancers. Colony-stimulating factor-1 (CSF-1) is expressed by many tumors and is a growth factor for macrophages and mediates osteoclast differentiation. Herein, we report the efficacy of a novel orally active CSF-1 receptor (CSF-1R) kinase inhibitor, JNJ-28312141, in proof of concept studies of solid tumor growth and tumor-induced bone erosion. H460 lung adenocarcinoma cells did not express CSF-1R and were not growth inhibited by JNJ-28312141 in vitro. Nevertheless, daily p.o. administration of JNJ-28312141 caused dose-dependent suppression of H460 tumor growth in nude mice that correlated with marked reductions in F4/80(+) tumor-associated macrophages and with increased plasma CSF-1, a possible biomarker of CSF-1R inhibition. Furthermore, the tumor microvasculature was reduced in JNJ-28312141-treated mice, consistent with a role for macrophages in tumor angiogenesis. In separate studies, JNJ-28312141 was compared with zoledronate in a model in which MRMT-1 mammary carcinoma cells inoculated into the tibias of rats led to severe cortical and trabecular bone lesions. Both agents reduced tumor growth and preserved bone. However, JNJ-28312141 reduced the number of tumor-associated osteoclasts superior to zoledronate. JNJ-28312141 exhibited additional activity against FMS-related receptor tyrosine kinase-3 (FLT3). To more fully define the therapeutic potential of this new agent, JNJ-28312141 was evaluated in a FLT3-dependent acute myeloid leukemia tumor xenograft model and caused tumor regression. In summary, this novel CSF-1R/FLT3 inhibitor represents a new agent with potential therapeutic activity in acute myeloid leukemia and in settings where CSF-1-dependent macrophages and osteoclasts contribute to tumor growth and skeletal events.