RESUMEN
Despite the extensive literature describing the role of the ATP-gated P2X(3) receptors in a variety of physiological processes the potential of antagonists as therapeutic agents has been limited by the lack of drug-like selective molecules. In this paper we report the discovery and optimization of RO-85, a novel drug-like, potent and selective P2X(3) antagonist. High-throughput screening of the Roche compound collection identified a small hit series of heterocyclic amides from a large parallel synthesis library. Rapid optimization, facilitated by high-throughput synthesis, focusing on increasing potency and improving drug-likeness resulted in the discovery of RO-85.
Asunto(s)
Descubrimiento de Drogas/métodos , Antagonistas del Receptor Purinérgico P2 , Pirazoles/química , Pirazoles/metabolismo , Pirazoles/farmacología , Tiofenos/química , Tiofenos/metabolismo , Tiofenos/farmacología , Animales , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Unión Proteica/fisiología , Ratas , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X3 , Relación Estructura-ActividadRESUMEN
Retinoid X receptor:peroxisome proliferative-activated receptor (RXR:PPAR) heterodimers play a critical role in the regulation of glucose (RXR/PPARgamma) and lipid metabolism (RXR/PPARalpha). Previously, we described a concise structure-activity relationship study of selective RXR modulators possessing a (2E,4E,6Z)-3-methyl-7-(3,5-dialkyl-6-alkoxyphenyl)-octa-2,4,6-trienoic acid scaffold. These studies were focused on the 2-position alkoxy side chain. We describe here the design and synthesis of a novel series of RXR selective modulators possessing the same aromatic core structure with the addition of a ring locked 6-7-Z-olefin on the trienoic acid moiety. The synthesis and structure-activity relationship studies of these 6,7-locked cyclopentenyl, phenyl, thienyl, furan, and pyridine-trienoic acid derivatives is presented herein.
Asunto(s)
Derivados del Benceno/química , Derivados del Benceno/farmacología , Caprilatos/química , Caprilatos/farmacología , Tiazolidinedionas , Alquenos/química , Alquenos/farmacología , Animales , Derivados del Benceno/síntesis química , Caprilatos/síntesis química , Línea Celular , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Sinergismo Farmacológico , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Masculino , Ratones , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Ácido Retinoico/agonistas , Receptores de Ácido Retinoico/antagonistas & inhibidores , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Receptores X Retinoide , Rosiglitazona , Relación Estructura-Actividad , Tiazoles/farmacología , Tiroxina/sangre , Factores de Transcripción/agonistas , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transfección , Triglicéridos/sangreRESUMEN
A series of androgen receptor modulators based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones was synthesized and evaluated in an androgen receptor transcriptional activation assay. The most potent analogues from the series exhibited single-digit nanomolar potency in vitro. Compound 18h demonstrated full efficacy in the maintenance of muscle weight, at 10 mg/kg, with reduced activity in prostate weight in an in vivo model of androgen action.
Asunto(s)
Oxazinas/síntesis química , Oxazinas/farmacología , Quinolonas/síntesis química , Quinolonas/farmacología , Receptores Androgénicos/efectos de los fármacos , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Indicadores y Reactivos , Masculino , Modelos Moleculares , Orquiectomía , Ratas , Receptores Androgénicos/química , Receptores de Progesterona/química , Receptores de Progesterona/efectos de los fármacos , Receptores de Somatotropina/química , Receptores de Somatotropina/efectos de los fármacos , Relación Estructura-Actividad , Testosterona/sangreRESUMEN
New RXR-selective modulators possessing a 6-fluoro trienoic acid moiety (6Z olefin) or a fluorinated/heterocyclic-substituted benzene core ring, were synthesized in an expedient and selective way. A subset of these compounds was evaluated for their metabolic properties (exposure in IRC male mice) and show a dramatic increase of exposure compared to our reference compound, 3 (LG101506).