RESUMEN
PPAR ligands with varied subtype selectivity have been synthesized using an achiral aminomethyl dihydrocinnamate template. Several compounds in this series have demonstrated potent plasma glucose and triglyceride lowering capability in rodent models of type 2 diabetes.
Asunto(s)
Cinamatos/síntesis química , Cinamatos/farmacocinética , Receptores Activados del Proliferador del Peroxisoma/fisiología , Humanos , Hipoglucemiantes/uso terapéutico , Ligandos , PPAR alfa/fisiología , PPAR gamma/fisiología , Relación Estructura-Actividad , Tiazolidinedionas/síntesis química , Tiazolidinedionas/uso terapéuticoRESUMEN
The synthesis of the peroxime proliferator activated receptor (PPAR) alpha,gamma-agonist (1) was accomplished with high enantio- and diastereoselectivity by employing an asymmetric hydrogenation strategy, of an alpha-alkoxy cinnamic acid derivative, to set the C-2 chiral center. A diastereospecific S(N)2 displacement under mild basic conditions established the C-10 stereochemistry without any detectable racemization of the two epimerizable chiral centers.
Asunto(s)
Cinamatos/química , Técnicas Químicas Combinatorias , PPAR alfa/agonistas , PPAR gamma/agonistas , Propionatos/síntesis química , Hidrogenación , Estructura Molecular , Propionatos/química , Propionatos/farmacología , EstereoisomerismoRESUMEN
Herein we describe a series of potent and selective PPARgamma agonists with moderate PPARalpha affinity and little to no affinity for other nuclear receptors. In vivo studies in a NIDDM animal model (ZDF rat) showed that these compounds are efficacious at low doses in glucose normalization and plasma triglyceride reduction. Compound 1b (LY519818) was selected from our SAR studies to be advanced to clinical evaluation for the treatment of type II diabetes.