RESUMEN
To further explore the optimum placement of the acid moiety in conformationally constrained analogs of GW 4064 1a, a series of stilbene replacements were prepared. The benzothiophene 1f and the indole 1g display the optimal orientation of the carboxylate for enhanced FXR agonist potency.
Asunto(s)
Isoxazoles/química , Isoxazoles/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Estilbenos/química , Estilbenos/farmacología , Secuencia de Aminoácidos , Animales , Línea Celular , Humanos , Conformación Molecular , Datos de Secuencia Molecular , Receptores Citoplasmáticos y Nucleares/metabolismoRESUMEN
Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.
Asunto(s)
Isoxazoles/química , Naftalenos/química , Receptores Citoplasmáticos y Nucleares/agonistas , Tiofenos/química , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Humanos , Isoxazoles/farmacología , Naftalenos/farmacocinética , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Relación Estructura-Actividad , Tiofenos/farmacocinéticaRESUMEN
A series of estrogen receptor ligands based on a 3-alkyl naphthalene scaffold was synthesized using an intramolecular enolate-alkyne cycloaromatization as the key step. Several of these compounds bearing a C6-OH group were shown to be high affinity ligands. All compounds had similar ERalpha and ERbeta binding affinity ranging from micromolar to low nanomolar.
Asunto(s)
Naftalenos/síntesis química , Naftalenos/farmacología , Receptores de Estrógenos/agonistas , Técnicas Químicas Combinatorias , Moduladores de los Receptores de Estrógeno/metabolismo , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Femenino , Humanos , Ligandos , Estructura Molecular , Naftalenos/química , Moduladores Selectivos de los Receptores de Estrógeno/metabolismo , Relación Estructura-ActividadRESUMEN
Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.
