RESUMO
A series of indane acetic acid derivatives were prepared which show a spectrum of activity as insulin sensitizers and PPAR-alpha and PPAR-delta ligands. In vivo data are presented for insulin sensitizers with selectivity for PPAR-delta over PPAR-alpha.
Assuntos
Resistência à Insulina , PPAR delta/agonistas , Transferência Ressonante de Energia de Fluorescência , Relação Estrutura-AtividadeRESUMO
Compounds that simultaneously activate the three peroxisome proliferator-activated receptor (PPAR) subtypes alpha, gamma, and delta hold potential to address the adverse metabolic and cardiovascular conditions associated with diabetes and the metabolic syndrome. We recently identified the indanylacetic acid moiety as a well-tunable PPAR agonist head group. Here we report the synthesis and structure-activity relationship (SAR) studies of novel aryl tail group derivatives that led to a new class of potent PPAR pan agonists. While most of the tail group modifications imparted potent PPAR delta agonist activity, improvement of PPAR alpha and gamma activity required the introduction of new heterocyclic substituents that were not known in the PPAR literature. Systematic optimization led to the discovery of 4-thiazolyl-phenyl derivatives with potent PPAR alpha/gamma/delta pan agonistic activity. The lead candidate from this series was found to exhibit excellent ADME properties and superior therapeutic potential compared to known PPAR gamma activating agents by favorably modulating lipid levels in hApoA1 mice and hyperlipidemic hamsters, while normalizing glucose levels in diabetic rodent models.
Assuntos
Acetatos/síntese química , Hipoglicemiantes/síntese química , Indanos/síntese química , PPAR alfa/agonistas , PPAR delta/agonistas , PPAR gama/agonistas , Triazóis/síntese química , Acetatos/química , Acetatos/farmacologia , Animais , Apolipoproteína A-I/genética , Linhagem Celular , Cricetinae , Feminino , Humanos , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Técnicas In Vitro , Indanos/química , Indanos/farmacologia , Lipídeos/sangue , Masculino , Camundongos , Camundongos Transgênicos , PPAR alfa/genética , PPAR gama/genética , Ensaio Radioligante , Ratos , Ratos Zucker , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Ativação Transcricional , Triazóis/química , Triazóis/farmacologiaRESUMO
Modulation of PPAR activities represents an attractive approach for the treatment of diabetes with associated cardiovascular complications. The indanylacetic acid structural motif has proven useful in the generation of potent and tunable PPAR ligands. Modification of the substituents on the linker and the heterocycle tail group allowed for the modulation of the selectivity at the different receptor subtypes. Compound 33 was evaluated in vivo, where it displayed the desired reduction of glucose levels and increase in HDL levels in various animal models.
