RESUMEN

In an effort to find new and safer treatments for osteoporosis and frailty, we describe a novel series of selective androgen receptor modulators (SARMs). Using a structure-based approach, we identified compound 7, a potent AR (ARE EC50 = 0.34 nM) and selective (N/C interaction EC50 = 1206 nM) modulator. In vivo data, an AR LBD X-ray structure of 7, and further insights from modeling studies of ligand receptor interactions are also presented.

Asunto(s)

Anabolizantes/química , Andrógenos/química , Nitrilos/química , Pirroles/química , Receptores Androgénicos/metabolismo , Anabolizantes/síntesis química , Anabolizantes/farmacocinética , Anabolizantes/farmacología , Andrógenos/síntesis química , Andrógenos/farmacocinética , Andrógenos/farmacología , Animales , Cristalografía por Rayos X , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Masculino , Simulación del Acoplamiento Molecular , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Nitrilos/síntesis química , Nitrilos/farmacología , Tamaño de los Órganos/efectos de los fármacos , Especificidad de Órganos , Próstata/efectos de los fármacos , Próstata/fisiología , Pirroles/síntesis química , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Vesículas Seminales/efectos de los fármacos , Vesículas Seminales/fisiología , Relación Estructura-Actividad

RESUMEN

Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB binding protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization that paid particular attention to physiochemical properties delivered chemical probes with desirable potency, selectivity, and permeability attributes. An important feature of the optimization process was the successful application of rational structure-based drug design to address bromodomain selectivity issues (particularly against the structurally related BRD4 protein).

Asunto(s)

Proteína de Unión a CREB/antagonistas & inhibidores , Diseño de Fármacos , Proteína p300 Asociada a E1A/antagonistas & inhibidores , Morfolinas/farmacología , Proteína de Unión a CREB/metabolismo , Química Farmacéutica , Relación Dosis-Respuesta a Droga , Proteína p300 Asociada a E1A/metabolismo , Humanos , Estructura Molecular , Morfolinas/síntesis química , Morfolinas/química , Relación Estructura-Actividad

RESUMEN

Bromodomains are involved in transcriptional regulation through the recognition of acetyl lysine modifications on diverse proteins. Selective pharmacological modulators of bromodomains are lacking, although the largely hydrophobic nature of the pocket makes these modules attractive targets for small-molecule inhibitors. This work describes the structure-based design of a highly selective inhibitor of the CREB binding protein (CBP) bromodomain and its use in cell-based transcriptional profiling experiments. The inhibitor downregulated a number of inflammatory genes in macrophages that were not affected by a selective BET bromodomain inhibitor. In addition, the CBP bromodomain inhibitor modulated the mRNA level of the regulator of G-protein signaling 4 (RGS4) gene in neurons, suggesting a potential therapeutic opportunity for CBP inhibitors in the treatment of neurological disorders.

Asunto(s)

Proteína de Unión a CREB/antagonistas & inhibidores , Diseño de Fármacos , Bibliotecas de Moléculas Pequeñas/química , Proteína de Unión a CREB/genética , Transferencia Resonante de Energía de Fluorescencia , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Estructura Terciaria de Proteína , Proteínas RGS/genética , Bibliotecas de Moléculas Pequeñas/farmacología , Transcriptoma

Asunto(s)

Biomarcadores Farmacológicos/química , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Sondas Moleculares/química , Biomarcadores Farmacológicos/metabolismo , Permeabilidad de la Membrana Celular , Humanos , Sondas Moleculares/metabolismo , Terapia Molecular Dirigida , Relación Estructura-Actividad , Estudios de Validación como Asunto

RESUMEN

In an effort to develop potent, orally bioavailable compounds for the treatment of neoplastic diseases, we developed a class of dual VEGFR-2 kinase and tubulin inhibitors. Targeting the VEGFR receptor kinase and tubulin structure allows for inhibition of both tumor cells and tumor vasculature. Previously, a combination of two compounds, a VEGF receptor tyrosine kinase inhibitor and tubulin agent, was demonstrated to produce an enhanced antitumor response in animal studies. We have reaffirmed their results, with the added benefit that both activities are found in one compound.