RESUMEN
This letter describes the discovery, synthesis, SAR, and biological activity of [2.2.1]-bicyclic sultams as potent antagonists of the androgen receptor. Optimization of the series led to the identification of compound 25, which displayed robust pharmacodynamic effects in rats after oral dosing.
Asunto(s)
Antagonistas de Receptores Androgénicos/química , Antagonistas de Receptores Androgénicos/farmacología , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/farmacología , Naftalenosulfonatos/química , Naftalenosulfonatos/farmacología , Administración Oral , Antagonistas de Receptores Androgénicos/farmacocinética , Animales , Compuestos Bicíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos con Puentes/farmacocinética , Línea Celular Tumoral , Humanos , Modelos Moleculares , Naftalenosulfonatos/administración & dosificación , Naftalenosulfonatos/farmacocinética , Ratas , Receptores Androgénicos/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of 4-[3,5-dioxo-11-oxa-4,9-diazatricyclo[5.3.1.0(2,6)]undec-4-yl]-2-trifluoromethyl-benzonitriles has been synthesized. The ability of these compounds to act as antagonists of the androgen receptor was investigated and several were found to have potent activity in vitro and in vivo.
Asunto(s)
Antineoplásicos/síntesis química , Nitrilos/química , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Diseño de Fármacos , Humanos , Masculino , Nitrilos/síntesis química , Nitrilos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Relación Estructura-ActividadRESUMEN
Hit to Lead optimization and SAR development led to the identification of the potent and selective benzo[d]imidazole inhibitor (17b) of Co-activator Associated Arginine Methyltransferase (CARM1).
Asunto(s)
Antineoplásicos/química , Bencimidazoles/química , Inhibidores Enzimáticos/química , Piperidinas/química , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Proteína-Arginina N-Metiltransferasas/metabolismo , Relación Estructura-ActividadRESUMEN
Design, synthesis, and SAR development led to the identification of the potent, novel, and selective pyrazole based inhibitor (7f) of Coactivator Associated Arginine Methyltransferase (CARM1).
Asunto(s)
Inhibidores Enzimáticos/química , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Pirazoles/química , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Proteína-Arginina N-Metiltransferasas/metabolismo , Pirazoles/síntesis química , Pirazoles/farmacología , Relación Estructura-ActividadRESUMEN
This study reports the identification and Hits to Leads optimization of inhibitors of coactivator associated arginine methyltransferase (CARM1). Compound 7b is a potent, selective inhibitor of CARM1.
Asunto(s)
Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Pirazoles/síntesis química , Pirazoles/farmacología , Técnicas Químicas Combinatorias , Estructura Molecular , Pirazoles/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel series of [2.2.1]-oxabicyclo imide-based compounds were identified as potent antagonists of the androgen receptor. Molecular modeling and iterative drug design were applied to optimize this series. The lead compound [3aS-(3aalpha,4beta,5beta,7beta,7aalpha)]-4-(octahydro-5-hydroxy-4,7-dimethyl-1,3-dioxo-4,7-epoxy-2H-isoindol-2-yl)-2-iodobenzonitrile was shown to have potent in vivo efficacy after oral dosing in the CWR22 human prostate tumor xenograph model.
Asunto(s)
Antagonistas de Receptores Androgénicos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Isoindoles/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Administración Oral , Antagonistas de Andrógenos/farmacología , Anilidas/farmacología , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Cromatografía Líquida de Alta Presión , Diseño de Fármacos , Humanos , Isoindoles/síntesis química , Isoindoles/farmacocinética , Masculino , Ratones , Ratones Endogámicos BALB C , Modelos Moleculares , Estructura Molecular , Nitrilos/farmacología , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Unión Proteica , Receptores Androgénicos/metabolismo , Relación Estructura-Actividad , Compuestos de Tosilo/farmacología , Células Tumorales CultivadasRESUMEN
A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). SAR around this series revealed dramatic differences in binding and function in mutant variants (MT) of the AR as compared to the wild type (WT) receptor. Optimization of the aniline portion revealed substitution patterns, which yielded potent antagonist activity against the WT AR as well as the MT AR found in the LNCaP and PCa2b human prostate tumor cell lines.
Asunto(s)
Antagonistas de Andrógenos/farmacología , Antagonistas de Receptores Androgénicos , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Indoles/química , Animales , Humanos , Concentración 50 Inhibidora , Masculino , Mutación , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A novel series of isoindoledione based compounds were identified as potent antagonists of the androgen receptor (AR). Co-crystallization of members of this family of inhibitors was successfully accomplished with the T877A AR LBD. A working model of how this class of compounds functions to antagonize the AR was created. Based on this model, it was proposed that expanding the bicyclic portion of the molecule should result in analogs which function as effective antagonists against a variety of AR isoforms. In contrast to what was predicted by the model, SAR around this new series was dictated by the aniline portion rather than the bicyclic portion of the molecule.
Asunto(s)
Antagonistas de Andrógenos/síntesis química , Indoles/química , Antagonistas de Andrógenos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Indoles/farmacología , Isoformas de Proteínas , Receptores Androgénicos/metabolismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A novel series of [2.2.1]-azahydantoins has been designed and synthesized in an enantiospecific manner. The ability of these compounds to act as antagonists to the androgen receptor was investigated and several were found to have potent activity in vitro.
Asunto(s)
Antagonistas de Receptores Androgénicos , Compuestos Aza/síntesis química , Compuestos Aza/farmacología , Hidantoínas/síntesis química , Hidantoínas/farmacología , Compuestos Aza/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Estudios de Evaluación como Asunto , Humanos , Hidantoínas/química , Modelos Moleculares , Conformación Molecular , Relación Estructura-ActividadRESUMEN
Prostate-specific antigen (PSA) is the most valuable marker for the evaluation of prostate cancer progression. The expression of PSA is controlled by androgen receptor (AR) through its binding to androgen-response elements (AREs). Several AREs have been identified within the 5.8-kb PSA promoter. The main activity of this 5.8-kb PSA promoter resides in a 455-bp enhancer core region located about 4 kb upstream of the TATA box. Our study suggests that in addition to the four AREs identified in the PSA enhancer core, another regulatory element (GAGATA), which is located at the region designated PSA3.1, also contributes to transcriptional regulation by androgens. Furthermore, electrophoretic mobility shift assay revealed that a putative transcriptional factor bound the GAGATA sequence in the PSA-producing prostate cancer cell. Further studies demonstrated that GAGATA factor preferentially bound the (G/C)(A/C/T)GATA sequence. The replacement of ATA with GGG in the GAGATA sequence completely eliminated the androgen-mediated transcriptional activity of the enhancer core. By using DNA-coupled magnetic beads and the Southwestern method, a 56-60-kDa protein was identified as the putative GAGATA binding factor. EMSA and Western blotting assay suggested that AR is not involved in androgen-mediated activation through PSA3.1. Therefore, we propose that binding of the GAGATA binding factor and AR to GAGATA and AREs, respectively, of the PSA enhancer core are required for the maximum transcriptional response to androgens.