RESUMO
A series of potent amide linked PPARgamma/delta dual agonists (1a) has been discovered through rational design. In the ZDF rat model of type 2 diabetes, compound (R)-3-[4-(3-{1-[(5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid (42) from this series has demonstrated glucose lowering efficacy comparable to the marketed PPARgamma agonist rosiglitazone with less weight gain.
Assuntos
Amidas/química , Desenho de Fármacos , Indóis/síntese química , PPAR delta/agonistas , PPAR gama/agonistas , Animais , Técnicas de Química Combinatória , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Indóis/química , Indóis/farmacologia , Estrutura Molecular , RatosRESUMO
The design and synthesis of the dual peroxisome proliferator-activated receptor (PPAR) gamma/delta agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment of type 2 diabetes and associated dyslipidemia is described. The compound possesses a potent dual hPPAR gamma/delta agonist profile (IC(50) = 19 nM/4 nM; EC(50) = 102 nM/6 nM for hPPARgamma and hPPARdelta, respectively). In preclinical models, the compound improves insulin sensitivity and reverses diabetic hyperglycemia with less weight gain at a given level of glucose control relative to rosiglitazone.
Assuntos
Hipoglicemiantes/síntese química , PPAR delta/agonistas , PPAR gama/agonistas , Éteres Fenílicos/síntese química , Fenilpropionatos/síntese química , Aumento de Peso/efeitos dos fármacos , Animais , Glicemia/metabolismo , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Dislipidemias/tratamento farmacológico , Feminino , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Camundongos , PPAR alfa/genética , Éteres Fenílicos/química , Éteres Fenílicos/farmacologia , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Ensaio Radioligante , Estereoisomerismo , Ativação TranscricionalRESUMO
A novel nonthiazolidinedione dual peroxisome proliferator- activated receptor (PPAR)-alpha/gamma agonist, LY465608, was designed to address the major metabolic disturbances of type 2 diabetes. LY465608 altered PPAR-responsive genes in liver and fat of db/db mice and dose-dependently lowered plasma glucose in hyperglycemic male Zucker diabetic fatty (ZDF) rats, with an ED(50) for glucose normalization of 3.8 mg small middle dot kg(-1) small middle dot day(-1). Metabolic improvements were associated with enhanced insulin sensitivity, as demonstrated in female obese Zucker (fa/fa) rats using both oral glucose tolerance tests and hyperinsulinemic-euglycemic clamps. Further characterization of LY465608 revealed metabolic changes distinct from a selective PPAR-gamma agonist, which were presumably due to the concomitant PPAR-alpha agonism, lower respiratory quotient, and less fat accumulation, despite a similar impact on glycemia in male ZDF rats. In addition to these alterations in diabetic and insulin-resistant animals, LY465608 dose-dependently elevated HDL cholesterol and lowered plasma triglycerides in human apolipoprotein A-I transgenic mice, demonstrating that this compound significantly improves primary cardiovascular risk factors. Overall, these studies demonstrate that LY465608 beneficially impacts multiple facets of type 2 diabetes and associated cardiovascular risk, including those facets involved in the development of micro- and macrovascular complications, which are the major sources for morbidity and mortality in these patients.
Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Síndrome Metabólica/fisiologia , Compostos Orgânicos , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazolidinedionas , Fatores de Transcrição/agonistas , Animais , Glicemia/efeitos dos fármacos , Proteínas de Ligação a DNA/agonistas , Diabetes Mellitus Tipo 2/sangue , Relação Dose-Resposta a Droga , Ingestão de Energia/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Teste de Tolerância a Glucose , Masculino , Camundongos , Camundongos Mutantes , Ratos , Ratos Zucker , Rosiglitazona , Tiazóis/uso terapêuticoRESUMO
The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR alpha/gamma agonist profile (IC(50) = 28 and 10 nM; EC(50) = 9 and 4 nM, respectively, for hPPARalpha and hPPARgamma). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.
Assuntos
Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Fenilpropionatos/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Tiofenos/síntese química , Fatores de Transcrição/agonistas , Animais , Ligação Competitiva , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Ensaio Radioligante , Ratos , Ratos Zucker , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologiaRESUMO
The design and synthesis of dual PPAR gamma/delta agonist (R)-3-{2-ethyl-4-[3-(4-ethyl-2-pyridin-2-yl-phenoxy)-butoxy]-phenyl}propionic acid is described. This compound dose-dependently lowered plasma glucose in hyperglycemic male Zucker diabetic fatty (ZDF) rats and produced less weight gain relative to rosiglitazone at an equivalent level of glucose control.
Assuntos
Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , PPAR delta/agonistas , PPAR gama/agonistas , Animais , Glicemia/metabolismo , Relação Dose-Resposta a Droga , Desenho de Fármacos , Feminino , Meia-Vida , Humanos , Hipoglicemiantes/farmacocinética , Indicadores e Reagentes , Insulina/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Rosiglitazona , Relação Estrutura-Atividade , Tiazolidinedionas/farmacologia , Aumento de Peso/efeitos dos fármacosRESUMO
The oxysterol receptors LXR (liver X receptor)-alpha and LXRbeta are nuclear receptors that play a key role in regulation of cholesterol and fatty acid metabolism. We found that LXRs also play a significant role in glucose metabolism. Treatment of diabetic rodents with the LXR agonist, T0901317, resulted in dramatic reduction of plasma glucose. In insulin-resistant Zucker (fa/fa) rats, T0901317 significantly improved insulin sensitivity. Activation of LXR did not induce robust adipogenesis but rather inhibited the expression of several genes involved in hepatic gluconeogenesis, including phosphoenolpyruvate carboxykinase (PEPCK). Hepatic glucose output was dramatically reduced as a result of this regulation. Nuclear run-on studies indicated that transcriptional repression was primarily responsible for the inhibition of PEPCK by the LXR agonist. In addition, we show that the regulation of the liver gluconeogenic pathway by LXR agonists was a direct effect on hepatocytes. These data not only suggest that LXRs are novel targets for diabetes but also reveal an unanticipated role for these receptors, further linking lipid and glucose metabolism.
Assuntos
Anticolesterolemiantes/farmacologia , Gluconeogênese/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Fígado/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Proteínas de Ligação a DNA , Relação Dose-Resposta a Droga , Feminino , Hidrocarbonetos Fluorados , Fígado/metabolismo , Receptores X do Fígado , Masculino , Camundongos , Receptores Nucleares Órfãos , Ratos , Ratos Zucker , SulfonamidasRESUMO
To understand the species selectivity in a series of alpha-methyl-alpha-phenoxy carboxylic acid PPARalpha/gamma dual agonists (1-11), structure-based molecular modeling was carried out in the ligand binding pockets of both human and mouse PPARalpha. This study suggested that interaction of both 4-phenoxy and phenyloxazole substituents of these ligands with F272 and M279 in mouse PPARalpha leads to the species-specific divergence in ligand binding. Insights obtained in the molecular modeling studies of these key interactions resulted in the ability to convert a human-selective PPARalpha agonist to a human and mouse dual agonist within the same platform.