RESUMO
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.
Assuntos
Cinamatos/síntese química , Cinamatos/farmacocinética , Receptores Ativados por Proliferador de Peroxissomo/fisiologia , Humanos , Hipoglicemiantes/uso terapêutico , Ligantes , PPAR alfa/fisiologia , PPAR gama/fisiologia , Relação Estrutura-Atividade , Tiazolidinedionas/síntese química , Tiazolidinedionas/uso terapêuticoRESUMO
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.
Assuntos
Cinamatos/química , Técnicas de Química Combinatória , PPAR alfa/agonistas , PPAR gama/agonistas , Propionatos/síntese química , Hidrogenação , Estrutura Molecular , Propionatos/química , Propionatos/farmacologia , EstereoisomerismoRESUMO
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.