RESUMEN
The therapeutic and toxic effects of drugs are often generated through effects on distinct cell types in the body. Selective delivery of drugs to specific cells or cell lineages would, therefore, have major advantages, in particular, the potential to significantly improve the therapeutic window of an agent. Cells of the monocyte-macrophage lineage represent an important target for many therapeutic agents because of their central involvement in a wide range of diseases including inflammation, cancer, atherosclerosis, and diabetes. We have developed a versatile chemistry platform that is designed to enhance the potency and delivery of small-molecule drugs to intracellular molecular targets. One facet of the technology involves the selective delivery of drugs to cells of the monocyte-macrophage lineage, using the intracellular carboxylesterase, human carboxylesterase-1 (hCE-1), which is expressed predominantly in these cells. Here, we demonstrate selective delivery of many types of intracellularly targeted small molecules to monocytes and macrophages by attaching a small esterase-sensitive chemical motif (ESM) that is selectively hydrolyzed within these cells to a charged, pharmacologically active drug. ESM versions of histone deacetylase (HDAC) inhibitors, for example, are extremely potent anticytokine and antiarthritic agents with a wider therapeutic window than conventional HDAC inhibitors. In human blood, effects on monocytes (hCE-1-positive) are seen at concentrations 1000-fold lower than those that affect other cell types (hCE-1-negative). Chemical conjugates of this type, by limiting effects on other cells, could find widespread applicability in the treatment of human diseases where monocyte-macrophages play a key role in disease pathology.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Esterasas/antagonistas & inhibidores , Esterasas/química , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Aminoácidos/química , Animales , Anisomicina/farmacología , Artritis/inmunología , Carboxilesterasa/antagonistas & inhibidores , Carboxilesterasa/química , Carboxilesterasa/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citocinas/biosíntesis , Citocinas/sangre , Citocinas/genética , Inhibidores Enzimáticos/farmacología , Esterasas/genética , Ésteres/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lipopolisacáridos/farmacología , Espectroscopía de Resonancia Magnética , Ratones , Ratones Transgénicos , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/sangre , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
Divinyl ketones bearing alpha-ester or alpha-amide groups undergo Nazarov cyclizations to give cylopentenones using copper-bisoxazoline Lewis acid complexes with moderate to good ees. [reaction: see text]
RESUMEN
A novel series of HDAC inhibitors demonstrating class I subtype selectivity and good oral bioavailability is described. The compounds are potent enzyme inhibitors (IC50 values less than 100 nM), and improved activity in cell proliferation assays was achieved by modulation of polar surface area (PSA) through the introduction of novel linking groups. Employing oral pharmacokinetic studies in mice, comparing drug levels in spleen to plasma, we selected compounds that were tested for efficacy in human tumor xenograft studies based on their potential to distribute into tumor. One compound, 21r (CHR-3996), showed good oral activity in these models, including dose-related activity in a LoVo xenograft. In addition 21r showed good activity in combination with other anticancer agents in in vitro studies. On the basis of these results, 21r was nominated for clinical development.
Asunto(s)
Antineoplásicos/síntesis química , Compuestos de Azabiciclo/síntesis química , Inhibidores de Histona Desacetilasas/síntesis química , Pirimidinas/síntesis química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Compuestos de Azabiciclo/farmacocinética , Compuestos de Azabiciclo/farmacología , Línea Celular Tumoral , Perros , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Femenino , Inhibidores de Histona Desacetilasas/farmacocinética , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Técnicas In Vitro , Ratones , Ratones Desnudos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Trasplante de Neoplasias , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Distribución Tisular , Trasplante HeterólogoRESUMEN
A novel p38 MAP kinase inhibitor structural class was discovered through selectivity screening. The rational analogue design, synthesis and structure-activity relationship of this series of bis-amide inhibitors is reported. The inhibition in vitro of human p38alpha enzyme activity and lipopolysaccharide-induced tumour necrosis factor-alpha release is described for the series. The activity in vivo and pharmacokinetic properties are exemplified for the more potent analogues.