RESUMEN
We have developed a pharmacophore model for the EP(3) receptor antagonists based on its endogenous ligand PGE(2). This ligand-based design yielded a series of novel peri-substituted [4.3.0] bicyclic aromatics featuring 1-alklyaryl 7-heterocyclic sulfonamide substituents. The synthesized molecules are potent antagonists of human EP(3) receptor in vitro and show inhibition of rat platelets aggregation. Optimized derivatives display high selectivity over IP, FP, and other EP receptor panels.
Asunto(s)
Compuestos Heterocíclicos/farmacología , Indoles/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Sulfonamidas/farmacología , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Humanos , Indoles/síntesis química , Indoles/química , Modelos Moleculares , Estructura Molecular , Subtipo EP3 de Receptores de Prostaglandina E , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
A series of peri-substituted [4.3.0] bicyclic non-aromatic heterocycles have been identified as potent and selective hEP(3) receptor antagonists. These molecules adopt a hair-pin conformation that overlaps with the endogenous ligand PGE(2) and fits into an internally generated EP(3) pharmacophore model. Optimized compounds show good metabolic stability and improved solubility over their corresponding bicyclic aromatic analogs.
Asunto(s)
Indoles/síntesis química , Indoles/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Alprostadil/análogos & derivados , Alprostadil/metabolismo , Animales , Células CHO , Química Farmacéutica/métodos , Cricetinae , Cricetulus , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ligandos , Espectroscopía de Resonancia Magnética , Prostaglandinas/química , Receptores de Prostaglandina E/química , Subtipo EP3 de Receptores de Prostaglandina E , Sulfonamidas/químicaRESUMEN
A series of potent and selective EP(3) receptor antagonists are described. Utilizing a pharmacophore model developed for the EP(3) receptor, a series of 3,4-disubstituted indoles were found to be efficient ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors. An optimized molecule 7c featured a sound profile and potency in the functional rat and human platelet aggregation assays.
Asunto(s)
Acrilamidas/síntesis química , Acrilamidas/metabolismo , Indoles/síntesis química , Indoles/metabolismo , Receptores de Prostaglandina E/antagonistas & inhibidores , Acrilamidas/farmacología , Animales , Células CHO , Cricetinae , Cricetulus , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Estabilidad de Medicamentos , Haplorrinos , Humanos , Indoles/farmacología , Ratones , Ratas , Receptores de Prostaglandina E/metabolismo , Subtipo EP3 de Receptores de Prostaglandina ERESUMEN
A series of potent and selective EP(3) receptor antagonists are described. Utilizing a pharmacophore model developed for the EP(3) receptor, a series of 3,4-disubstituted indoles were shown to be high affinity ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors and are potent antagonists in functional assays.