RESUMO
The synthesis and in vitro characterization of novel RXR-selective ligands possessing various substituted 1-benzofuran or 1-benzothiophene moieties are described.
Assuntos
Desenho de Fármacos , Receptores do Ácido Retinoico/metabolismo , Fatores de Transcrição/metabolismo , Tretinoína/análogos & derivados , Tretinoína/metabolismo , Ligação Proteica/fisiologia , Receptores X de Retinoides , Relação Estrutura-AtividadeRESUMO
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.
