RESUMO
Patients with type 2 diabetes mellitus exhibit hyperglycemia and dyslipidemia as well as a markedly increased incidence of atherosclerotic cardiovascular disease. Here we report the characterization of a novel arylthiazolidinedione capable of lowering both glucose and lipid levels in animal models. This compound, designated TZD18, is a potent agonist with dual human peroxisome proliferator-activated receptor (PPAR)-alpha/gamma activities. In keeping with its PPARgamma activity, TZD18 caused complete normalization of the elevated glucose in db/db mice and Zucker diabetic fatty rats. TZD18 lowered both cholesterol and triglycerides in hamsters and dogs. TZD18 inhibited cholesterol biosynthesis at steps before mevalonate and reduced hepatic levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Moreover, TZD18 significantly suppressed gene expression of fatty acid synthesis and induced expression of genes for fatty acid degradation and triglyceride clearance. Studies on 17 additional PPARalpha or PPARalpha/gamma agonists showed that lipid lowering in hamsters correlated with the magnitude of hepatic gene expression changes. Importantly, the presence of PPARgamma agonism did not affect the relationship between hepatic gene expression and lipid lowering. Taken together, these data suggest that PPARalpha/gamma agonists, such as TZD18, affect lipid homeostasis, leading to an antiatherogenic plasma lipid profile. Agents with these properties may provide favorable means for treatment of type 2 diabetes and dyslipidemia and the prevention of atherosclerotic cardiovascular disease.
Assuntos
Homeostase/efeitos dos fármacos , Hipolipemiantes/farmacologia , Metabolismo dos Lipídeos , Éteres Fenílicos/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazolidinedionas/farmacologia , Fatores de Transcrição/agonistas , Animais , Glicemia/metabolismo , Células COS , Colesterol/biossíntese , Colesterol/sangue , Cricetinae , Diabetes Mellitus/sangue , Cães , Expressão Gênica/efeitos dos fármacos , Humanos , Hidroximetilglutaril-CoA Redutases/efeitos dos fármacos , Hidroximetilglutaril-CoA Redutases/metabolismo , Lipídeos/sangue , Fígado/metabolismo , Masculino , Mesocricetus , Camundongos , Obesidade/sangue , Éteres Fenílicos/química , RNA Mensageiro/metabolismo , Ratos , Ratos Zucker , Tiazolidinedionas/química , Triglicerídeos/antagonistas & inibidores , Triglicerídeos/sangue , Triglicerídeos/metabolismoRESUMO
A series of chromane-2-carboxylic acid derivatives was synthesized and evaluated for PPAR agonist activities. A structure-activity relationship was developed toward PPARalpha/gamma dual agonism. As a result, (2R)-7-(3-[2-chloro-4-(4-fluorophenoxy)phenoxy]propoxy)-2-ethylchromane-2-carboxylic acid (48) was identified as a potent, structurally novel, selective PPARalpha/gamma dual agonist. Compound 48 exhibited substantial antihyperglycemic and hypolipidemic activities when orally administered in three different animal models: the db/db mouse type 2 diabetes model, a Syrian hamster lipid model, and a dog lipid model.
Assuntos
Benzopiranos/síntese química , Cromanos/síntese química , Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Éteres Fenílicos/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Animais , Benzopiranos/química , Benzopiranos/farmacocinética , Benzopiranos/farmacologia , Cromanos/química , Cromanos/farmacocinética , Cromanos/farmacologia , Cricetinae , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Cães , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Macaca mulatta , Masculino , Mesocricetus , Camundongos , Éteres Fenílicos/química , Éteres Fenílicos/farmacocinética , Éteres Fenílicos/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Transativadores/síntese química , Transativadores/química , Transativadores/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
A SAR study was conducted on chromane-2-carboxylic acid toward selective PPARalpha agonisim. As a result, highly potent, and selective PPARalpha agonists were discovered. The optimized compound 43 exhibited robust lowering of total cholesterol levels in hamster and dog animal models.
Assuntos
Ácidos Carboxílicos/farmacologia , Cromanos/farmacologia , Hipolipemiantes/farmacologia , PPAR alfa/agonistas , Animais , Ácidos Carboxílicos/administração & dosagem , Ácidos Carboxílicos/síntese química , Cromanos/administração & dosagem , Cromanos/síntese química , Cricetinae , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Hipolipemiantes/administração & dosagem , Hipolipemiantes/síntese química , Macaca mulatta , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
Here, we characterize the actions of MK-0767, a dual ligand of the nuclear receptors peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma. In cell-based assays, MK-0767 produced potent activation of human PPARgamma and PPARalpha with a gamma:alpha potency ratio of approximately 2. The dual agonist induced high affinity interactions of PPARalpha and PPARgamma with the transcriptional coactivator CBP in vitro. In ob/ob mice, MK-0767 normalized hyperglycemia and hyperinsulinemia with equal or greater potency and efficacy than pioglitazone. Treatment of hamsters with MK-0767 produced substantial reductions in blood cholesterol and triglycerides. In dogs, MK-0767 reduced serum cholesterol levels with a potency more than 10-fold greater than simvastatin. The efficacies of MK-0767 and simvastatin were additive when given together. We conclude that MK-0767 is a potent dual PPARalpha/gamma agonist with robust insulin sensitizing and hypolipidemic activities.