RESUMEN
The design, synthesis and pharmacological properties of a novel class of PPARalpha agonists is described. Compound 2 is a novel, potent and specific glycine amide with oral bioavailability in rodents. The compound is active in vivo and alters plasma lipids in hAPO-A1 transgenic mice after oral administration.
Asunto(s)
Glicina/análogos & derivados , PPAR alfa/agonistas , Animales , Disponibilidad Biológica , Glicina/farmacocinética , Glicina/farmacología , Ratones , Ratones Transgénicos , Relación Estructura-ActividadRESUMEN
Palladium catalyzed asymmetric allylic alkylation reaction of an amine with two equivalents of butadiene monoxide allows for the expedient synthesis of trans- and cis-2,5-dihydropyrroles. The versatility of these chiral synthons towards the synthesis of a wide variety of iminosugar natural products was demonstrated with the short and high yielding asymmetric syntheses of (+)-DMDP, and (-)-bulgecinine. In addition, the first total synthesis of (+)-broussonetine G, a potent glycosidase inhibitor, is described along with the assignment of its relative and absolute stereochemical configuration.
Asunto(s)
Alcaloides/síntesis química , Compuestos Epoxi/química , Glicopéptidos/síntesis química , Manitol/análogos & derivados , Pirrolidinas/síntesis química , Alcaloides/química , Alquilación , Catálisis , Glicopéptidos/química , Iminopiranosas/síntesis química , Iminopiranosas/química , Manitol/síntesis química , Manitol/química , Resonancia Magnética Nuclear Biomolecular , Paladio/química , Pirrolidinas/química , EstereoisomerismoRESUMEN
We report the solid-phase synthesis and pharmacological evaluation of a new series of small-molecule agonists of the human peroxisome proliferator-activated receptor delta (PPARdelta) based on a lead structure from our PPARalpha program. Compound 33 showed good pharmacokinetics.
Asunto(s)
PPAR alfa/agonistas , PPAR delta/agonistas , Relación Estructura-ActividadRESUMEN
Novel heterocycle-fused thyromimetics are presented carrying indoles or indazoles instead of the phenolic group in T3. Potent agonists were identified in both series. SAR trends are examined and found to be mostly consistent with previously published thyromimetics. Moderate THRbeta selectivity (approx. 10-fold) was observed in the indole series using isoform-selective transient THR transfection assays.