RESUMEN
We successfully discovered peptidomimetic motilin antagonists (17c and 17d) through the improvement of physicochemical properties of a tetrapeptide antagonist (2). Furthermore, with oral administration and based on motilin antagonistic activity, both compounds suppressed motilin-induced colonic and gastric motility in conscious dogs.
Asunto(s)
Fármacos Gastrointestinales/antagonistas & inhibidores , Motilina/antagonistas & inhibidores , Oligopéptidos/síntesis química , Péptidos/química , Animales , Células CACO-2 , Línea Celular , Descubrimiento de Drogas , Fármacos Gastrointestinales/metabolismo , Humanos , Motilina/metabolismo , Oligopéptidos/química , Oligopéptidos/farmacología , Péptidos/síntesis química , Permeabilidad , Conejos , RatasRESUMEN
The 3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethylthiohydantoin derivatives which have carboxy-terminal side chains were synthesized and their agonistic/antagonistic activities against androgen receptor (AR) measured. Among them, compound 13b showed antagonistic activity (IC50=130 nM) with no agonistic activity even at 10000 nM. This compound exhibited significant metabolic stability and oral antiandrogenic activity (ED50=7 mg/kg).
Asunto(s)
Antagonistas de Andrógenos/síntesis química , Antagonistas de Andrógenos/farmacología , Antagonistas de Receptores Androgénicos , Animales , Unión Competitiva/efectos de los fármacos , Células CHO , Cricetinae , Cricetulus , Cristalografía por Rayos X , Genes Reporteros/efectos de los fármacos , Células HeLa , Humanos , Indicadores y Reactivos , Masculino , Ratones , Ratones Endogámicos ICR , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Vesículas Seminales/efectos de los fármacos , Relación Estructura-Actividad , Tiohidantoínas/síntesis química , Tiohidantoínas/farmacologíaRESUMEN
Lead optimization of CH4892280 (4), an androgen receptor (AR) pure antagonist, was investigated. Compounds 6 and 7, which have a carboxylic acid at the end of the side chain at the position 7alpha of dihydrotestosterone (DHT), showed partial agonistic activities in reporter gene assay (RGA). Conversion of the steroidal core structure to 17alpha-methyltestosterone gave compound 14, which showed weak pure antagonistic activity. Optimization of the side chain by the insertion of a phenyl ring led to compounds 22 and 28-30, which showed pure antagonistic activities at submicromolar concentrations. The structure-activity relationships were clarified.
Asunto(s)
Antagonistas de Receptores Androgénicos , Receptores Androgénicos/metabolismo , Esteroides/química , Esteroides/farmacología , Animales , Ratones , Modelos Moleculares , Estructura Molecular , Unión Proteica , Receptores Androgénicos/química , Esteroides/síntesis química , Relación Estructura-ActividadRESUMEN
A series of 7alpha-substituted dihydrotestosterone derivatives were synthesized and evaluated for androgen receptor (AR) pure antagonistic activity. From reporter gene assay (RGA), the compound with a side chain containing N-n-butyl-N-methyl amide (19a) showed pure antagonistic activity (IC(50)=340nM, FI(5)>10,000nM), whereas known AR antagonists showed partial agonistic activities. The optimization of 19a led to compound 23 (CH4892280), which showed more potent pure antagonistic activity (IC(50)=190nM, FI(5)>10,000nM). The SARs of tested compounds suggested that the length of the side chain and the substituents on the amide nitrogen are important for pure antagonistic activities.