RESUMEN
Oxobenzimidazoles (e.g., 1), a novel series of androgen receptor (AR) antagonists, were discovered through de novo design guided by structure-based drug design. The compounds in this series were reasonably permeable and metabolically stable, but suffered from poor solubility. The incorporation of three dimensional structural features led to improved solubility. In addition, the observation of a 'flipped' binding mode of an oxobenzimidazole analog in an AR ligand binding domain (LBD) model, led to the design and discovery of the novel oxindole series (e.g., 2) that is a potent full antagonist of AR.
Asunto(s)
Antagonistas de Receptores Androgénicos/síntesis química , Antineoplásicos/síntesis química , Bencimidazoles/síntesis química , Indoles/síntesis química , Receptores Androgénicos/química , Antagonistas de Receptores Androgénicos/farmacología , Antineoplásicos/farmacología , Bencimidazoles/farmacología , Línea Celular Tumoral , Diseño de Fármacos , Descubrimiento de Drogas , Humanos , Indoles/farmacología , Ligandos , Masculino , Modelos Moleculares , Neoplasias de la Próstata , Unión Proteica , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Receptores Androgénicos/metabolismo , Solubilidad , Relación Estructura-ActividadRESUMEN
High throughput cell-based screening led to the identification of 3-aryloxy lactams as potent androgen receptor (AR) antagonists. Refinement of these leads to improve the ADME profile and remove residual agonism led to the discovery of 12, a potent full antagonist with greater oral bioavailability. Improvements in the ADME profile were realized by designing more ligand-efficient molecules with reduced molecular weights and lower lipophilicities.
Asunto(s)
Descubrimiento de Drogas , Lactamas/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/química , Relación Dosis-Respuesta a Droga , Ensayos Analíticos de Alto Rendimiento , Humanos , Lactamas/síntesis química , Lactamas/química , Masculino , Modelos Moleculares , Estructura Molecular , Neoplasias de la Próstata/cirugía , Receptores Androgénicos/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy. This strategy allowed for further optimization of potency leading to the discovery of the clinical candidate PF-915275.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Aminopiridinas/síntesis química , Inhibidores Enzimáticos/síntesis química , Sulfonamidas/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Aminopiridinas/química , Aminopiridinas/farmacocinética , Animales , Línea Celular , Simulación por Computador , Cricetinae , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMEN
An aryloxy tetramethylcyclobutane was identified as a novel template for androgen receptor (AR) antagonists via cell-based high-throughput screening. Follow-up to the initial "hit" established 5 as a viable lead. Further optimization to achieve full AR antagonism led to the discovery of 26 and 30, both of which demonstrated excellent in vivo tumor growth inhibition upon oral administration in a castration-resistant prostate cancer (CRPC) animal model.