RESUMEN
A novel series of cyanoguanidine-piperazine P2X(7) antagonists was designed based upon the structure of A-740003. Structure-activity relationship (SAR) studies focused on the piperazine moiety and the right hand side substitution. Compounds were assayed for activity at human and rat P2X(7) receptors and compound 29 was found to possess potent activity (IC(50)=30-60 nM) at both species.
Asunto(s)
Piperazinas/síntesis química , Piperazinas/farmacología , Antagonistas del Receptor Purinérgico P2 , Proteínas Recombinantes/antagonistas & inhibidores , Animales , Humanos , Técnicas In Vitro , Estructura Molecular , Ratas , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X7 , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of cyanoguanidine-piperazine P2X(7) antagonists were identified and structure-activity relationship (SAR) studies described. Compounds were assayed for activity at human and rat P2X(7) receptors in addition to their ability to inhibit IL-1 beta release from stimulated human whole blood cultures. Compound 27 possesses potent activity (0.12 microM) in this latter assay and demonstrates moderate clearance in-vivo.
Asunto(s)
Guanidinas/química , Piperazinas/química , Antagonistas del Receptor Purinérgico P2 , Animales , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Interleucina-1beta/antagonistas & inhibidores , Modelos Químicos , Estructura Molecular , Piperazina , Ratas , Receptores Purinérgicos P2/química , Receptores Purinérgicos P2X7 , Relación Estructura-ActividadRESUMEN
The reactivity of a range of pyridone and pyrazinone derivatives towards alkynes in the presence of cyclopentadienylcobaltbis(ethene) has been investigated. Depending on the nature of the substrates, [2+2+2]- or [2+2] cycloaddition, C-H, or N-H activation may occur. In the case of pyridones, the first three predominated with N-protected derivatives, whereas substrates containing N-H bonds followed an N-H activation pathway. The [2+2+2] cycloaddition of an N-butynylisoquinolone was applied successfully to the total synthesis of anhydrolycorinone. Pyrazinone substrates showed similar patterns of reactivity.
Asunto(s)
Alquinos/química , Cobalto/química , Pirazinas/química , Piridonas/química , Cristalografía por Rayos X , Ciclización , Indicadores y Reactivos , Isocianatos/química , Modelos Moleculares , Nitrilos/química , Oxidación-ReducciónRESUMEN
We describe the identification, SAR, and in vivo pharmacology of a new series of Src-family selective Lck inhibitors. These thienopyridines were designed based on a desire to access the unique residues in the extended hinge region of Lck.