RESUMO
A new series of thiazole-substituted 1,1,1,3,3,3-hexafluoro-2-propanols were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Key analogs caused dose-dependent decreases in food intake and body weight in obese mice. Acute treatment with these compounds also led to a drop in elevated blood glucose in a murine model of type II diabetes.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Carboxiliases/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Desenho de Fármacos , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Propanóis/uso terapêutico , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Carboxiliases/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Propanóis/síntese química , Propanóis/química , Propanóis/farmacologia , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia , Tiazóis/uso terapêuticoRESUMO
A series of highly functionalized 3-aroyl and 3-phenoxy-2-methyl-7-azaindoles have been identified, which are potent selective PPARgamma modulators (SPPARgammaMs). Addition of substituents at the 6-position of the 7-azaindoles improves in vitro potency and pharmacokinetics. 7-Azaindoles have significantly improved off-target profiles compared to the parent indole series.
Assuntos
Indóis/química , Indóis/farmacologia , PPAR gama/metabolismo , Animais , Humanos , Camundongos , PPAR gama/agonistas , Ratos , Ratos Sprague-DawleyRESUMO
Peroxisome proliferator-activated receptor (PPAR)-gamma agonists are insulin sensitizers, whereas PPAR alpha agonists are lipid-lowering agents in humans. Chronic treatment with PPAR gamma agonists has been shown to prevent the onset of diabetes in young Zucker diabetic fatty (ZDF) rats; however, the effects of PPAR alpha agonists have not been well characterized in this model. Here we investigated chronic efficacy of PPAR alpha and nonthiazolidinedione (nTZD) PPAR gamma agonists on the onset of diabetes in 6-wk-old male ZDF rats. Whereas treatment with the nTZD PPAR gamma agonist completely prevented development of hyperglycemia, PPAR alpha activation was associated with lowering of food intake and body weight and reductions in fed and fasting hyperglycemia, with prevention of the hyperinsulinemic peak preceding the development of hyperglycemia in ZDF rats. Both compounds improved glucose tolerance during an oral glucose tolerance test with concomitant increases in insulin response. Such improvements of insulin secretion were associated with increased islet to total pancreatic area ratio and pancreatic insulin contents. Hyperinsulinemic-euglycemic clamp studies demonstrated that nTZD PPAR gamma reduced basal endogenous glucose production and increased insulin-stimulated glucose disposal, consistent with an improved insulin action as a cause of the improved glucose homeostasis. In contrast, activation of PPAR alpha did not significantly improve glucose metabolism during the hyperinsulinemic-euglycemic clamp. In conclusion, chronic treatment of ZDF rats with a PPAR gamma agonist completely prevented the onset of diabetes by improving both insulin action and secretion, whereas PPAR alpha agonism was partially effective, primarily by improving the pancreatic islet insulin response. Unlike the PPAR gamma agonist, the PPAR alpha agonist demonstrated efficacy without inducing body weight gain and cardiomegaly. This study suggests a possible role for PPAR alpha agonists in the prevention of type 2 diabetes mellitus.
Assuntos
Diabetes Mellitus Tipo 2/prevenção & controle , PPAR alfa/agonistas , PPAR gama/agonistas , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Jejum , Alimentos , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Homeostase , Hiperglicemia/prevenção & controle , Insulina/sangue , Insulina/farmacologia , Ilhotas Pancreáticas/patologia , Masculino , Músculo Esquelético/química , PPAR alfa/farmacologia , Ratos , Ratos Zucker , Triglicerídeos/análiseRESUMO
A series of 2-aryloxy-2-methyl-propionic acid compounds and related analogues were designed, synthesized, and evaluated for their PPAR agonist activities. 2-[(5,7-Dipropyl-3-trifluoromethyl)-benzisoxazol-6-yloxy]-2-methylpropionic acid (4) was identified as a PPARalpha/gamma dual agonist with relative PPARalpha selectivity and demonstrated potent efficacy in lowering both glucose and lipids in animal models without causing body weight gain. The PPARalpha activity of 4 appeared to have played a significant role in lowering glucose levels in db/db mice.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Isoxazóis/síntese química , PPAR alfa/agonistas , PPAR gama/agonistas , Propionatos/síntese química , Células 3T3-L1 , Animais , Glicemia/efeitos dos fármacos , Células COS , Proteínas de Transporte/biossíntese , Proteínas de Transporte/genética , Chlorocebus aethiops , Colesterol/sangue , Cães , Proteínas de Ligação a Ácido Graxo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Isoxazóis/química , Isoxazóis/farmacologia , Camundongos , Camundongos Obesos , Propionatos/química , Propionatos/farmacologia , RNA Mensageiro/biossíntese , Ensaio Radioligante , Relação Estrutura-Atividade , Ativação Transcricional , Triglicerídeos/sangue , Aumento de PesoRESUMO
The synthesis and structure-activity relationships of novel series of alpha-aryloxyphenylacetic acids as PPARalpha/gamma dual agonists are reported. The initial search for surrogates of the ester group in the screen lead led first to the optimization of a subseries with a ketone moiety. Further efforts to modify the ketone subseries led to the design and synthesis of two new subseries containing fused heterocyclic ring systems. All these analogues were characterized by their "super" PPARalpha agonist activity and weak or partial agonist activity on PPARgamma in PPAR-GAL4 transactivation assays despite their similar binding affinities for both receptors. The cocrystal structures of compounds 7 and rosiglitazone with PPARgamma-LBD were compared, and significant differences were found in their interactions with the receptor. Select analogues in each subseries were further evaluated for in vivo efficacy. They all showed excellent anti-hyperglycemic efficacy in a db/db mouse model and hypolipidemic activity in hamster and dog models without provoking the typical PPARgamma-associated side effects in the rat tolerability assay.
Assuntos
Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , PPAR alfa/agonistas , PPAR delta/agonistas , Fenilacetatos/síntese química , Animais , Cricetinae , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cães , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Cinética , Masculino , Mesocricetus , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Modelos Moleculares , Estrutura Molecular , Fenilacetatos/química , Fenilacetatos/farmacocinética , Fenilacetatos/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Antidiabetic thiazolidinediones (TZDs) and non-TZD compounds have been shown to serve as agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma). Here, we report the identification and characterization of a novel non-TZD selective PPARgamma modulator (nTZDpa). nTZDpa bound potently to PPARgamma with high selectivity vs. PPARalpha or PPARdelta. In cell-based assays for transcriptional activation, nTZDpa served as a selective, potent PPARgamma partial agonist and was able to antagonize the activity of PPARgamma full agonists. nTZDpa also displayed partial agonist effects when its ability to promote adipogenesis in 3T3-L1 cells was evaluated. Assessment of protein conformation using protease protection or solution nuclear magnetic resonance spectroscopy methods showed that nTZDpa produced altered PPARgamma conformational stability vs. full agonists, thereby establishing a physical basis for its observed partial agonism. DNA microarray analysis of RNA from 3T3-L1 adipocytes treated with nTZDpa or several structurally diverse PPARgamma full agonists demonstrated qualitative differences in the affected gene expression profile for nTZDpa. Chronic treatment of fat-fed, C57BL/6J mice with nTZDpa or a TZD full agonist ameliorated hyperglycemia and hyperinsulinemia. However, unlike the TZD, nTZDpa caused reductions in weight gain and adipose depot size. Feed efficiency was also substantially diminished. Unlike TZDs, nTZDpa did not cause cardiac hypertrophy in mice. When a panel of PPARgamma target genes was examined in white adipose tissue, nTZDpa produced a different in vivo expression pattern vs. the full agonist. These findings establish that novel selective PPARgamma modulators can produce altered receptor conformational stability leading to distinctive gene expression profiles, reduced adipogenic cellular effects, and potentially improved in vivo biological responses. Such compounds may lead to preferred therapies for diabetes, obesity, or metabolic syndrome.
Assuntos
Indóis/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/química , Sulfetos/farmacologia , Fatores de Transcrição/agonistas , Fatores de Transcrição/química , Adipócitos/efeitos dos fármacos , Adipócitos/fisiologia , Tecido Adiposo/efeitos dos fármacos , Animais , Cardiomegalia/induzido quimicamente , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Resistência à Insulina , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Conformação Proteica , Aumento de Peso/efeitos dos fármacosRESUMO
PPAR gamma is an adipocyte-specific nuclear hormone receptor. Agonists of PPAR gamma, such as thiazolidinediones (TZDs), promote adipocyte differentiation and have insulin-sensitizing effects in animals and diabetic patients. Affymetrix oligonucleotide arrays representing 6347 genes were employed to profile the gene expression responses of mature 3T3-L1 adipocytes and differentiating preadipocytes to a TZD PPAR gamma agonist in vitro. The expression of 579 genes was significantly up- or down-regulated by more than 1.5-fold during differentiation and/or by treatment with TZD, and these genes were organized into 32 clusters that demonstrated concerted changes in expression of genes controlling cell growth or lipid metabolism. Quantitative PCR was employed to further characterize gene expression and led to the identification of beta-catenin as a new PPAR gamma target gene. Both mRNA and protein levels for beta-catenin were down-regulated in 3T3-L1 adipocytes compared with fibroblasts and were further decreased by treatment of adipocytes with PPAR gamma agonists. Treatment of db/db mice with a PPAR gamma agonist also resulted in reduction of beta-catenin mRNA levels in adipose tissue. These results suggest that beta-catenin plays an important role in the regulation of adipogenesis. Thus, the transcriptional patterns revealed in this study further the understanding of adipogenesis process and the function of PPAR gamma activation.
Assuntos
Adipócitos/fisiologia , Regulação da Expressão Gênica/fisiologia , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/fisiologia , Tiazolidinedionas , Transativadores , Fatores de Transcrição/agonistas , Fatores de Transcrição/fisiologia , Células 3T3 , Adipócitos/metabolismo , Algoritmos , Animais , Western Blotting , Diferenciação Celular , Células Cultivadas , Proteínas do Citoesqueleto/biossíntese , Proteínas do Citoesqueleto/genética , Regulação da Expressão Gênica/genética , Hipoglicemiantes/farmacologia , Hibridização In Situ , Metabolismo dos Lipídeos , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , Sondas de Oligonucleotídeos , Fenótipo , RNA , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rosiglitazona , Tiazóis/farmacologia , beta CateninaRESUMO
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 series of benzimidazolone carboxylic acids and oxazolidinediones were designed and synthesized in search of selective PPARγ modulators (SPPARγMs) as potential therapeutic agents for the treatment of type II diabetes mellitus (T2DM) with improved safety profiles relative to rosiglitazone and pioglitazone, the currently marketed PPARγ full agonist drugs. Structure-activity relationships of these potent and highly selective SPPARγMs were studied with a focus on their unique profiles as partial agonists or modulators. A variety of methods, such as X-ray crystallographic analysis, PPARγ transactivation coactivator profiling, gene expression profiling, and mutagenesis studies, were employed to reveal the differential interactions of these new analogues with PPARγ receptor in comparison to full agonists. In rodent models of T2DM, benzimidazolone analogues such as (5R)-5-(3-{[3-(5-methoxybenzisoxazol-3-yl)benzimidazol-1-yl]methyl}phenyl)-5-methyloxazolidinedione (51) demonstrated efficacy equivalent to that of rosiglitazone. Side effects, such as fluid retention and heart weight gain associated with PPARγ full agonists, were diminished with 51 in comparison to rosiglitazone based on studies in two independent animal models.
Assuntos
Benzimidazóis/síntese química , Dimetadiona/análogos & derivados , Hipoglicemiantes/síntese química , PPAR gama/metabolismo , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Sítios de Ligação , Células COS , Chlorocebus aethiops , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dimetadiona/síntese química , Dimetadiona/química , Dimetadiona/farmacologia , Agonismo Parcial de Drogas , Perfilação da Expressão Gênica , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Modelos Moleculares , Mutagênese , Coativadores de Receptor Nuclear/metabolismo , Oxazóis/síntese química , Oxazóis/química , Oxazóis/farmacologia , PPAR gama/agonistas , PPAR gama/genética , Pioglitazona , Conformação Proteica , Ratos , Ratos Zucker , Rosiglitazona , Relação Estrutura-Atividade , Tiazolidinedionas/química , Tiazolidinedionas/farmacologia , Ativação TranscricionalRESUMO
A series of 3-acylindole-1-benzylcarboxylic acids were designed and synthesized while searching for a PPARgamma modulator with additional moderate intrinsic PPARalpha agonistic activity. 2-[3-[[3-(4-Chlorobenzoyl)-2-methyl-6-(trifluoromethoxy)-1H-indol-1-yl]methyl]phenoxy]-(2R)-butanoic acid (12d) was identified as such an agent which demonstrated potent efficacy in lowering both glucose and lipids in multiple animal models with significantly attenuated side effects such as fluid retention and heart weight gain associated with PPARgamma full agonists. The moderate PPARalpha activity of 12d not only contributed to the agent's ability to manage lipid profiles but also appears to have potentiated its PPARgamma efficacy in lowering glucose levels in preclinical diabetic animal models.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Dislipidemias/tratamento farmacológico , PPAR gama/agonistas , PPAR gama/metabolismo , Animais , Glicemia/metabolismo , Ácido Butírico/síntese química , Ácido Butírico/química , Ácido Butírico/farmacologia , Ácido Butírico/uso terapêutico , Linhagem Celular , Colesterol/sangue , Cricetinae , Diabetes Mellitus Tipo 2/sangue , Cães , Dislipidemias/sangue , Feminino , Humanos , Indóis/química , Masculino , Camundongos , Ratos , Relação Estrutura-AtividadeRESUMO
Routine screening for human PPAR ligands yielded compounds 1 and 2, both of which were sub-micromolar hPPARgamma agonists. Synthetic modifications of these leads led to a series of potent substituted 3-benzyl-2-methyl indoles, a subset of which were noted to be selective PPARgamma modulators (SPPARgammaMs). SPPARgammaM 24 displayed robust anti-diabetic activity with an improved therapeutic window in comparison to a PPARgamma full agonist in a rodent efficacy model.
Assuntos
Mediadores da Inflamação/metabolismo , PPAR gama/agonistas , Animais , Benzoatos/síntese química , Benzoatos/farmacologia , Benzoatos/uso terapêutico , Diabetes Mellitus/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Indóis/síntese química , Indóis/farmacologia , Indóis/uso terapêutico , Ligantes , Estrutura Molecular , PPAR gama/metabolismoRESUMO
A series of amphipathic 3-phenylbenzisoxazoles were found to be potent agonists of human PPARalpha, gamma and delta. The optimization of acid proximal structure for in vitro and in vivo potency is described. Results of po dosed efficacy studies in the db/db mouse model of type 2 diabetes showed efficacy equal or superior to Rosiglitazone in correcting hyperglycemia and hypertriglyceridemia. Good functional receptor selectivity for PPARalpha and gamma over PPARdelta can be obtained.
Assuntos
Isoxazóis/química , Isoxazóis/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazolidinedionas , Fatores de Transcrição/agonistas , Administração Oral , Animais , Disponibilidade Biológica , Células COS , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Isoxazóis/farmacocinética , Camundongos , Camundongos Mutantes , Proteínas Nucleares/agonistas , Proteínas Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Rosiglitazona , Tiazóis/farmacocinética , Tiazóis/farmacologia , Fatores de Transcrição/metabolismoRESUMO
A new class of O-arylmandelic acid PPAR agonists show excellent anti-hyperglycemic efficacy in a db/db mouse model of DM2. These PPARalpha-weighted agonists do not show the typical PPARgamma associated side effects of BAT proliferation and cardiac hypertrophy in a rat tolerability assay.
Assuntos
Ácidos Mandélicos/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Animais , Ácidos Mandélicos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Ratos , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/metabolismoRESUMO
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.
Assuntos
Benzamidas/farmacologia , Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazóis/farmacologia , Fatores de Transcrição/agonistas , Animais , Benzamidas/química , Glicemia/análise , Células COS , Chlorocebus aethiops , Colesterol/sangue , Cricetinae , Cães , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Humanos , Hipoglicemiantes/química , Hipolipemiantes/química , Insulina/sangue , Masculino , Mesocricetus , Camundongos , Camundongos Obesos , Pioglitazona , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Sinvastatina/farmacologia , Tiazolidinedionas/farmacologia , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ativação Transcricional/efeitos dos fármacos , Triglicerídeos/sangueRESUMO
A novel series of 5-aryl thiazolidine-2,4-diones based dual PPARalpha/gamma agonists was identified. A number of highly potent and orally bioavailable analogues were synthesized. Efficacy study results of some of these analogues in the db/db mice model of type 2 diabetes showed them superior to rosiglitazone in correcting hyperglycemia and hypertriglyceridemia.
Assuntos
Hipoglicemiantes/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazolidinedionas/síntese química , Fatores de Transcrição/agonistas , Administração Oral , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Hiperglicemia/tratamento farmacológico , Hipertrigliceridemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Camundongos , Receptores Citoplasmáticos e Nucleares/metabolismo , Rosiglitazona , Relação Estrutura-Atividade , Tiazolidinedionas/farmacologia , Fatores de Transcrição/metabolismoRESUMO
A series of novel aryloxazolidine-2,4-diones was synthesized. A structure-activity relationship study of these compounds led to the identification of potent, orally active PPAR dual alpha/gamma agonists. Based on the results of efficacy studies in the db/db mice model of type 2 diabetes and the desired pharmacokinetic parameters, compound 12 was selected for further profiling.
Assuntos
Hipoglicemiantes/farmacologia , Oxazóis/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Administração Oral , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Oxazóis/química , Oxazóis/farmacocinética , Relação Estrutura-AtividadeRESUMO
A series of 5-aryl thiazolidine-2,4-diones containing 4-phenoxyphenyl side chains was designed, synthesized, and evaluated for PPAR agonist activities. One such compound 28 exhibited comparable levels of glucose correction to rosiglitazone in the db/db mouse type 2 diabetes animal model.