RESUMEN
Chemical starting points were investigated for downregulation of the androgen receptor as an approach to treatment of advanced prostate cancer. Although prototypic steroidal downregulators such as 6a designed for intramuscular administration showed insufficient cellular potency, a medicinal chemistry program derived from a novel androgen receptor ligand 8a led to 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (10b), for which high plasma levels following oral administration in a preclinical model compensate for moderate cellular potency.
Asunto(s)
Neoplasias de la Próstata/tratamiento farmacológico , Piridazinas/farmacología , Receptores Androgénicos/metabolismo , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Humanos , Ligandos , Masculino , Modelos Moleculares , Estructura Molecular , Peso Molecular , Neoplasias de la Próstata/metabolismo , Piridazinas/síntesis química , Piridazinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Substitution of phenyl oxazolidinones with carbon-linked azoles resulted in the discovery of a new class of potent oxazolidinones that have excellent Gram-positive activity. In addition, replacement of the C-5 acetamide side chains with a 4-methyl triazole diminished monoamine oxidase activity. The synthesis and biological evaluation of these compounds are reported.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Oxazolidinonas/síntesis química , Oxazolidinonas/farmacología , Animales , Antibacterianos/farmacocinética , Disponibilidad Biológica , Recuento de Colonia Microbiana , Femenino , Bacterias Grampositivas/efectos de los fármacos , Semivida , Humanos , Hígado/enzimología , Ratones , Ratones Endogámicos C57BL , Pruebas de Sensibilidad Microbiana , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/farmacología , Infecciones Neumocócicas/tratamiento farmacológico , Infecciones Neumocócicas/microbiología , Ratas , Streptococcus pneumoniae/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Oxazolidinones represent a new and promising class of antibacterial agents. Current research in this area is mainly concentrated on improving the safety profile and the antibacterial spectrum. Many oxazolidinones, including linezolid (marketed as Zyvox), are inhibitors of monoamine oxidase A (MAO-A), which presents an undesired side effect. Recently, it was found that the 1,2,3-triazole is a good replacement for the conventional acetamide functionality found in oxazolidinones. We now disclose the finding that 1,2,3-triazoles bearing a substituent like methyl, small substituted methyl, bromo, or a linear (sp-hybridized) group at the 4 position (compounds such as 5, 16, 19, and 21) are good antibacterials with reduced or no activity, within the detection limit of the assay, against MAO-A. The results are especially promising for the development of oxazolidinones with an improved safety profile. The MAO-A SAR can be rationalized on the basis of docking studies to a MAO-A/MAO-B homology model.
Asunto(s)
Antibacterianos/síntesis química , Inhibidores de la Monoaminooxidasa/síntesis química , Monoaminooxidasa/metabolismo , Oxazolidinonas/síntesis química , Triazoles/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Haemophilus influenzae/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacología , Oxazolidinonas/química , Oxazolidinonas/farmacología , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacologíaRESUMEN
Carbonylcobalt(0) species have been used as linkers between alkynes and a polymer support for the first time. The alkynes may be loaded indirectly onto a phosphine functionalised polymer via their hexacarbonyldicobalt(0) complex, or directly onto a cobalt coated polymer. The alkynes have been released either as alkynes, thus providing a traceless method of immobilising alkynes, or by reaction with an alkene to generate a cyclopentenone via the Pauson-Khand reaction. The cobalt coated polymers produced during this study were shown to catalyse the Pauson-Khand reaction.
