RESUMO
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.
Assuntos
Descoberta de Drogas/métodos , Antagonistas do Receptor Purinérgico P2 , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Tiofenos/química , Tiofenos/metabolismo , Tiofenos/farmacologia , Animais , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ligação Proteica/fisiologia , Ratos , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X3 , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Oxazinas/síntese química , Oxazinas/farmacologia , Quinolonas/síntese química , Quinolonas/farmacologia , Receptores Androgênicos/efeitos dos fármacos , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Indicadores e Reagentes , Masculino , Modelos Moleculares , Orquiectomia , Ratos , Receptores Androgênicos/química , Receptores de Progesterona/química , Receptores de Progesterona/efeitos dos fármacos , Receptores da Somatotropina/química , Receptores da Somatotropina/efeitos dos fármacos , Relação Estrutura-Atividade , Testosterona/sangueRESUMO
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).
Assuntos
Cumarínicos/síntese química , Cumarínicos/farmacologia , Receptores do Ácido Retinoico/fisiologia , Fatores de Transcrição/fisiologia , Animais , Ligação Competitiva , Linhagem Celular , Desenho de Fármacos , Cinética , Masculino , Camundongos , Receptores do Ácido Retinoico/efeitos dos fármacos , Receptor alfa de Ácido Retinoico , Receptores X de Retinoides , Fatores de Transcrição/efeitos dos fármacos , Tretinoína/farmacocinética , Receptor gama de Ácido RetinoicoRESUMO
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.