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1.
PLoS One ; 17(3): e0264974, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35245328

RESUMO

During recent years combining GLP-1 and glucagon receptor agonism with the purpose of achieving superior weight loss and metabolic control compared to GLP-1 alone has received much attention. The superior efficacy has been shown by several in preclinical models but has been difficult to reproduce in humans. In this paper, we present the pre-clinical evaluation of NN1177, a long-acting GLP-1/glucagon receptor co-agonist previously tested in clinical trials. To further investigate the contribution from the respective receptors, two other co-agonists (NN1151, NN1359) with different GLP-1-to-glucagon receptor ratios were evaluated in parallel. In the process of characterizing NN1177, species differences and pitfalls in traditional pre-clinical evaluation methods were identified, highlighting the translational challenges in predicting the optimal receptor balance in humans. In diet-induced obese (DIO) mice, NN1177 induced a dose-dependent body weight loss, primarily due to loss of fat mass, and improvement in glucose tolerance. In DIO rats, NN1177 induced a comparable total body weight reduction, which was in contrast mainly caused by loss of lean mass, and glucose tolerance was impaired. Furthermore, despite long half-lives of the three co-agonists, glucose control during steady state was seen to depend on compound exposure at time of evaluation. When evaluated at higher compound exposure, glucose tolerance was similarly improved for all three co-agonists, independent of receptor balance. However, at lower compound exposure, glucose tolerance was gradually impaired with higher glucagon receptor preference. In addition, glucose tolerance was found to depend on study duration where the effect of glucagon on glucose control became more evident with time. To conclude, the pharmacodynamic effects at a given GLP-1-to-glucagon ratio differs between species, depends on compound exposure and study length, complicating the identification of an optimally balanced clinical candidate. The present findings could partly explain the low number of clinical successes for this dual agonism.


Assuntos
Glucagon , Receptores de Glucagon , Animais , Glicemia/metabolismo , Glucagon/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Camundongos , Camundongos Obesos , Obesidade/metabolismo , Ratos , Receptores de Glucagon/metabolismo , Redução de Peso
2.
Chem Biol ; 14(11): 1294-303, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18022568

RESUMO

Dimeric positive allosteric modulators of ionotropic glutamate receptors were designed, synthesized, and characterized pharmacologically in electrophysiological experiments. The designed compounds are dimers of arylpropylsulfonamides and have been constructed without a linker. The monomeric arylpropylsulfonamides were derived from known modulators and target the cyclothiazide-binding site at the AMPA receptors. The three stereoisomers--R,R, meso, and S,S--of the two constructed dimers were prepared, and in vitro testing showed the R,R forms to be the most potent stereoisomers. The biarylpropylsulfonamides have dramatically increased potencies, more than three orders of magnitude higher than the corresponding monomers. Dimer (R,R)-2a was cocrystallized with the GluR2-S1S2J construct, and an X-ray crystallographic analysis showed (R,R)-2a to bridge two identical binding pockets on two neighboring GluR2 subunits. Thus, this is biostructural evidence of a homomeric dimer bridging two identical receptor-binding sites.


Assuntos
Receptores de AMPA/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Dimerização , Ligantes , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular , Conformação Proteica , Receptores de AMPA/química , Estereoisomerismo
3.
Eur J Pharmacol ; 596(1-3): 173-9, 2008 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-18761337

RESUMO

Balaglitazone is a novel thiazolidinedione in clinical development for the treatment of type 2 diabetes. Common side effects associated with PPARgamma receptor agonists are weight gain, oedema and adipogenesis. Balaglitazone is a selective partial PPARgamma agonist and it has been speculated that such compounds have a more favourable safety margin than full agonists. We have compared impact of equi-efficacious antihyperglycaemic doses of balaglitazone with full PPARgamma agonist rosiglitazone on body fluid accumulation, cardiac enlargement, and adipogenesis. Equi-efficacious antihyperglycaemic doses (ED(90)) of balaglitazone (3 mg/kg/day) and rosiglitazone (6 mg/kg/day) were determined in male diabetic db/db mice. In adult male rats treated for up to 42 days, feeding, drinking, anthropometry, and plasma volumes were measured. Total plasma volume was measured with dye dilution technique. Compared to vehicle, rosiglitazone consistently increased food intake throughout the 42 day treatment period. In contrast, balaglitazone increased food intake in the last week of the experiment. However, both rosiglitazone and balaglitazone increased water intake. After 42 days, rosiglitazone treated rats displayed significantly elevated adiposity. Rosiglitazone increased total blood and plasma volumes throughout the treatment. Twenty-one days of balaglitazone treatment had no significant impact on blood or plasma volumes, whilst 42 days of balaglitazone increased plasma volume but to a significantly lesser extent than seen for rosiglitazone (vehicle: 46.1+/-1.5; balaglitazone: 50.8+/-1.21; rosiglitazone: 54.6+/-1.6 ml/kg). Heart weight was significantly elevated only in rosiglitazone treated animals. At doses inducing comparable antihyperglycaemic control, the full PPARgamma agonist, rosiglitazone, induces more pronounced body fluid retention and heart enlargement than seen for the partial PPARgamma agonist, balaglitazone. Thus, partial agonists may pose safer alternative to current anti-diabetic therapy with full PPARgamma agonist.


Assuntos
Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , PPAR gama/agonistas , Quinazolinas/efeitos adversos , Quinazolinas/farmacologia , Tiazolidinedionas/efeitos adversos , Tiazolidinedionas/farmacologia , Adipogenia/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Animais , Volume Sanguíneo/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Coração/anatomia & histologia , Coração/efeitos dos fármacos , Humanos , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , PPAR gama/genética , Ratos , Rosiglitazona
4.
J Med Chem ; 50(7): 1495-503, 2007 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-17343371

RESUMO

The aim was to identify a novel selective PPARdelta agonist with full efficacy on free fatty acid (FFA) oxidation in vitro and plasma lipid correction in vivo. Using the triple PPARalpha,gamma,delta agonist 1 as the structural starting point, we wanted to investigate the possibility of obtaining selective PPARdelta agonists by modifying only the acidic part of 1, while holding the lipophilic half of the molecule constant. The structure-activity relationship was guided by in vitro transactivation data using the human PPAR receptors, FFA oxidation efficacy performed in the rat muscle L6 cell line, and in vivo rat pharmacokinetic properties. Compound 7 ([4-[3,3-bis-(4-bromo-phenyl)-allylthio]-2-chloro-phenoxy]-acetic acid) was identified as a selective, partial agonist with good oral pharmacokinetic properties in rat. Chronic treatment of high fat fed ApoB100/CETP-Tgn mice with 7 corrected the plasma lipid parameters and improved insulin sensitivity. These data suggest that selective PPARdelta agonists have the potential to become a novel treatment of dyslipidemia.


Assuntos
Compostos Alílicos/síntese química , Metabolismo dos Lipídeos/efeitos dos fármacos , PPAR delta/agonistas , Fenilacetatos/síntese química , Administração Oral , Compostos Alílicos/farmacocinética , Compostos Alílicos/farmacologia , Animais , Apolipoproteína B-100/genética , Sítios de Ligação , Linhagem Celular , Proteínas de Transferência de Ésteres de Colesterol/genética , Cristalografia por Raios X , Gorduras na Dieta/administração & dosagem , Ácidos Graxos não Esterificados/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Músculo Esquelético/citologia , Oxirredução , Fenilacetatos/farmacocinética , Fenilacetatos/farmacologia , Ratos , Relação Estrutura-Atividade , Ativação Transcricional
5.
Ann N Y Acad Sci ; 1067: 448-53, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16804025

RESUMO

Type 2 diabetes is a metabolic disease characterized by increased plasma glucose and insulin as well as dyslipidemia. If left untreated, chronic diseases will develop that are associated with neuropathic damage and higher mortality risk. Using a rational drug design, novel compounds have been developed that selectively activate the human PPAR receptors, leading to lessening of hyperglycemia and hyperinsulinemia as well as reduction of lipid levels in conjunction with an increase of the beneficial HDL-cholesterol. These PPAR agonists showed increased potency and efficacy compared to previously marketed insulin sensitizers. Lead compounds with desirable pharmacokinetic properties were chosen for further testing in several animal models. The in vivo activity of some synthetic ligands, capable of activating two or all three members of peroxisome proliferator-activated receptors (PPAR) family of receptors, suggested that they may have improved efficacy in type 2 diabetes therapy. Here, we briefly summarize the development of some novel PPAR agonists identified by our group in recent years.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Animais , Dislipidemias/tratamento farmacológico , Humanos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Modelos Biológicos , Receptores Ativados por Proliferador de Peroxissomo/classificação , Receptores Ativados por Proliferador de Peroxissomo/fisiologia
6.
J Med Chem ; 46(8): 1306-17, 2003 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-12672231

RESUMO

A new and improved synthesis of the peroxisome proliferator-activated receptor (PPAR) agonist ragaglitazar applicable for large-scale preparation has been developed. The convergent synthetic procedure was based on a novel enzymatic kinetic resolution step. The conformation of ragaglitazar bound to the hPPARgamma receptor was quite different compared to the single-crystal structures of the l-arginine salt of ragaglitazar. In particular, the phenoxazine ring system had varying orientations. Ragaglitazar had high affinity for the hPPARalpha and -gamma receptors with IC(50) values of 0.98 and 0.092 microM, respectively. The lack of hPPARdelta activity could be explained by the absence of binding in the tail-up pocket in the hPPARdelta receptor, in contrast to the hPPARdelta agonist GW2433, which was able to bind in both the tail-up and tail-down pockets of the receptor.


Assuntos
Hipoglicemiantes/síntese química , Oxazinas/síntese química , Fenilpropionatos/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Sítios de Ligação , Cristalografia por Raios X , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Ligantes , Modelos Moleculares , Oxazinas/química , Oxazinas/farmacologia , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Ensaio Radioligante , Estereoisomerismo
7.
J Med Chem ; 46(23): 4883-94, 2003 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-14584939

RESUMO

Two potent nonselective, but PPARalpha-preferring, PPAR agonists 5 and 6 were designed and synthesized in high yields. The concept of dimeric ligands in transcription factors was investigated by synthesizing and testing the corresponding dimers 7, 8a, and 8b in PPAR transactivation assays. The three dimeric ligands all showed agonist activity on all three PPAR receptor subtypes, but with different profiles compared to the monomers 5 and 6. Despite breaking all the "rule of five" criteria, the dimers had excellent oral bioavailability and pharmacokinetic properties, resulting in good in vivo efficacy in db/db mice. X-ray crystal structure and modeling experiments suggested that the dimers interacted with the AF-2 helix as well as with amino acid residues in the lipophilic pocket close to the receptor surface.


Assuntos
Alcenos/síntese química , Propionatos/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Fatores de Transcrição/agonistas , Alcenos/farmacocinética , Alcenos/farmacologia , Sequência de Aminoácidos , Animais , Sítios de Ligação , Disponibilidade Biológica , Linhagem Celular , Cristalografia por Raios X , Dimerização , Humanos , Ligantes , Masculino , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Propionatos/farmacocinética , Propionatos/farmacologia , Ratos , Receptores Citoplasmáticos e Nucleares/química , Receptores Citoplasmáticos e Nucleares/metabolismo , Alinhamento de Sequência , Estereoisomerismo , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Ativação Transcricional
8.
J Med Chem ; 45(4): 789-804, 2002 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-11831892

RESUMO

Synthesis and structure-activity relationships of tricyclic alpha-ethoxy-phenylpropionic acid derivatives guided by in vitro PPARalpha and PPARgamma transactivation data and computer modeling led to the identification of the novel carbazole analogue, 3q, with dual PPARalpha (EC(50) = 0.36 microM) and PPARgamma (EC(50) = 0.17 microM) activity in vitro. Ten days treatment of db/db mice with 3q improved the insulin sensitivity, as measured by OGTT, better than that seen with both pioglitazone and rosiglitazone treatment, suggesting in vivo PPARgamma activity. Likewise, 3q lowered plasma triglycerides and cholesterol in high cholesterol fed rats after 4 days treatment, indicating in vivo PPARalpha activity. Investigations of the pharmacokinetics of selected compounds suggested that extended drug exposure improved the in vivo activity of in vitro active compounds.


Assuntos
Carbazóis/síntese química , Hipoglicemiantes/síntese química , Hipolipemiantes/síntese química , Proteínas Nucleares/agonistas , Fenilpropionatos/síntese química , Receptores Citoplasmáticos e Nucleares/agonistas , Tiazolidinedionas , Fatores de Transcrição/agonistas , Animais , Glicemia/metabolismo , Carbazóis/química , Carbazóis/farmacocinética , Carbazóis/farmacologia , Colesterol/sangue , Colesterol na Dieta/administração & dosagem , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Teste de Tolerância a Glucose , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacologia , Masculino , Camundongos , Modelos Moleculares , Fenilpropionatos/química , Fenilpropionatos/farmacocinética , Fenilpropionatos/farmacologia , Pioglitazona , Ratos , Ratos Sprague-Dawley , Rosiglitazona , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacocinética , Tiazóis/farmacologia , Triglicerídeos/sangue
9.
ChemMedChem ; 7(3): 440-51, 2012 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-22267204

RESUMO

A series of compounds based on the mGluR5-selective ligand 2-methyl-6-(phenylethynyl)pyridine (MPEP) were designed and synthesized. The compounds were found to be either structural analogues of MPEP, substituted monomers, or dimeric analogues. All compounds retained mGluR5 selectivity with only weak or no activity at other mGluRs or iGluRs. The substituted analogue, 1,3-bis(pyridin-2-ylethynyl)benzene (19), is a potent negative modulator at mGluR5, whereas all other compounds lost potency relative to MPEP and showed that activity is highly dependent on the position of the nitrogen atom in the pyridine moieties. A homology modeling and ligand docking study was used to understand the binding mode and the observed selectivity of compound 19.


Assuntos
Alcinos/síntese química , Ansiolíticos/síntese química , Transtornos de Ansiedade/tratamento farmacológico , Piridinas/síntese química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Alcinos/farmacologia , Alcinos/uso terapêutico , Regulação Alostérica , Sequência de Aminoácidos , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Transtornos de Ansiedade/metabolismo , Sítios de Ligação , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Cricetinae , Dimerização , Ácido Glutâmico/metabolismo , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Ligação Proteica , Piridinas/farmacologia , Piridinas/uso terapêutico , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-Atividade
10.
Br J Pharmacol ; 163(3): 556-66, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21265823

RESUMO

BACKGROUND AND PURPOSE: The peroxisome proliferator-activated receptor (PPAR)δ has been considered a therapeutic target for diabetes and obesity through enhancement of fatty acid oxidation. The present study aimed to characterize the effects of PPARδ agonists during insulin resistance of the whole body, muscle and liver. EXPERIMENTAL APPROACH: Wistar rats and C57BL/J6 mice were fed a high fat diet (HF) and then treated with PPARδ agonists NNC61-5920 and GW501516. The effects on insulin resistance were evaluated by hyperinsulinaemic clamp or glucose tolerance tests combined with glucose tracers. KEY RESULTS: In HF rats, 3 weeks of treatment with NNC61-5920 reduced the glucose infusion rate (by 14%, P < 0.05) and glucose disposal into muscle (by 20-30%, P < 0.01) during hyperinsulinaemic clamp. Despite increased mRNA expression of carnitine palmitoyltransferase-1, pyruvate dehydrogenase kinase 4 and uncoupling protein 3 in muscle, plasma and muscle triglyceride levels were raised (P < 0.01). Similar metabolic effects were observed after extended treatment with NNC61-5920 and GW501516 to 6 weeks. However, HF mice treated with NNC61-5920 improved their plasma lipid profile, glucose tolerance and insulin action in muscle. In both HF rats and mice, NNC61-5920 treatment attenuated hepatic insulin resistance and decreased expression of stearoyl-CoA desaturase 1, fatty acid translocase protein CD36 and lipoprotein lipase in liver. CONCLUSIONS AND IMPLICATIONS: PPARδ agonists exacerbated insulin resistance in HF rats in contrast to their beneficial effects on metabolic syndrome in HF mice. These opposing metabolic consequences result from their different effects on lipid metabolism and insulin sensitivity in skeletal muscle of these two species.


Assuntos
Gorduras na Dieta/administração & dosagem , Resistência à Insulina , Músculo Esquelético/efeitos dos fármacos , PPAR delta/agonistas , Animais , Biomarcadores/metabolismo , Glucose/metabolismo , Teste de Tolerância a Glucose , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Especificidade de Órgãos , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Especificidade da Espécie , Tiazóis/farmacologia , Triglicerídeos/metabolismo
11.
Eur J Pharmacol ; 626(2-3): 297-305, 2010 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-19818749

RESUMO

The peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. Several reports have shown that PPARdelta is involved in lipid metabolism, increasing fat oxidation and depleting lipid accumulation. Whether PPARdelta is involved in the regulation of glucose metabolism is not completely understood. In this study, we examined effects of long-term PPARdelta activation on glycemic control, islet function and insulin sensitivity in diabetic db/db mice. Male db/db mice were administered orally once daily with a selective and partial PPARdelta agonist (NNC 61-5920, 30 mg/kg) for eight weeks; control mice received vehicle. Fasting and non-fasting plasma glucose were reduced, reflected in reduced hemoglobinA(1c) (3.6+/-1.6% vs. 5.4+/-1.8 in db/db controls, P<0.05) and furthermore, the AUC(glucose) after oral glucose (3g/kg) was reduced by 67% (P<0.05) after long-term PPARdelta activation. Following intravenous glucose (1g/kg), glucose tolerance was improved after PPARdelta activation (K(G) 1.3+/-0.6 vs. -0.05+/-0.7 %/min, P=0.048). Insulin sensitivity, measured as the glucose clearance after intravenous injection of glucose (1g/kg) and insulin (0.75 or 1.0 U/kg), during inhibition of endogenous insulin secretion by diazoxide (25mg/kg), was improved (K(G) 2.9+/-0.6 vs. 1.3+/-0.3 %/min in controls, P<0.05) despite lower insulin levels. Furthermore, islets isolated from PPARdelta agonist treated mice demonstrated improved glucose responsiveness as well as improved cellular topography. In conclusion, PPARdelta agonism alleviates insulin resistance and improves islet function and topography, resulting in improved glycemia in diabetic db/db mice. This suggests that activation of PPARdelta improves glucose metabolism and may therefore potentially be target for treatment of type 2 diabetes.


Assuntos
Diabetes Mellitus/fisiopatologia , Insulina/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/fisiopatologia , PPAR delta/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Ácidos Graxos não Esterificados/metabolismo , Glucose/metabolismo , Teste de Tolerância a Glucose , Humanos , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Oxirredução/efeitos dos fármacos , PPAR delta/agonistas , Palmitatos/metabolismo , Fatores de Tempo
12.
Bioorg Med Chem Lett ; 17(15): 4144-9, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17553681

RESUMO

Y-shaped molecules bearing alkynylallylic moieties were found to be potent and selective PPARdelta activators. The alkynylallylic moiety was synthesized from alkyn-1-ols by hydroalumination followed by a cross-coupling reaction. Series of active compounds 6 were obtained by stepwise changing the structure of the known PPARpan agonist 5 into Y-shaped compounds. The most active and selective compound, 6f, had a PPARdelta potency of 0.13 microM, which is 50-fold more potent than compound 5.


Assuntos
PPAR delta/agonistas , Modelos Moleculares , Estrutura Molecular
13.
Bioorg Med Chem Lett ; 17(16): 4625-9, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17560785

RESUMO

Structure based ligand design was used in order to design a partial agonist for the PPARdelta receptor. The maximum activation in the transactivation assay was reduced from 87% to 39%. The crystal structure of the ligand binding domain of the PPARdelta receptor in complex with compound 2 was determined in order to understand the structural changes which gave rise to the decrease in maximum activation.


Assuntos
Butiratos/química , Butiratos/farmacologia , PPAR delta/agonistas , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Desenho de Fármacos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 17(11): 3198-202, 2007 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-17379517

RESUMO

Computational analysis of the ligand binding pocket of the three PPAR receptor subtypes was utilized in the design of potent PPARalpha agonists. Optimum PPARalpha potency and selectivity were obtained with substituents having van der Waals volume around 260. Compound 6 had a PPARalpha potency of 0.002 microM and a selectivity ratio to PPARgamma and PPARdelta of 410 and 2000, respectively.


Assuntos
Desenho de Fármacos , PPAR alfa/agonistas , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Animais , Computadores , Cristalografia , Ligantes , PPAR alfa/química , Fenilpropionatos/síntese química
15.
Bioorg Med Chem Lett ; 15(5): 1497-500, 2005 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-15713415

RESUMO

A series of dimeric PPAR agonists were designed and tested for PPAR activity in vitro. The SAR showed that dimeric ligands with a common group or full dimeric ligands had retained or even increased PPARgamma potency. The dimeric agonist concept can be used to fine tune the subtype selectivity of PPAR agonists. The PPARgamma potency could, at least partly, be explained using molecular modeling.


Assuntos
Receptores Ativados por Proliferador de Peroxissomo/agonistas , Dimerização , Desenho de Fármacos , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Receptores Ativados por Proliferador de Peroxissomo/química , Relação Estrutura-Atividade
16.
J Lipid Res ; 45(3): 592-601, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14999041

RESUMO

Peroxisome proliferator-activated receptor (PPAR)-alpha controls the transcription of a variety of genes involved in lipid metabolism and is the target receptor for the hypolipidemic drug class of fibrates. In the present study, the molecular and physiological effects of seven different PPAR-activating drugs have been examined in a rodent model of dyslipidemia. The drugs examined were selected to display varying potencies and efficacies toward PPAR-alpha. To help elucidate the link between the gene regulation elicited by PPAR-alpha ligands and the concomitant physiological changes, we have used cDNA microarray analysis to identify smaller gene sets that are predictive of the function of these ligands. A number of genes showed strong correlations to the relative PPAR-alpha efficacy of the drugs. Furthermore, using multivariate analysis, a strong relationship between the drug-induced triglyceride lowering and the transcriptional profiles of the different drugs could be found.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Perfilação da Expressão Gênica , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/agonistas , Fatores de Transcrição/metabolismo , Animais , Apolipoproteínas C/sangue , Biomarcadores , Linhagem Celular , Colesterol na Dieta/farmacologia , Modelos Animais de Doenças , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/genética , Ligantes , Masculino , Estrutura Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Valor Preditivo dos Testes , RNA Mensageiro/análise , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/genética , Fatores de Transcrição/genética , Triglicerídeos/sangue
17.
Am J Physiol Endocrinol Metab ; 284(4): E841-54, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12475752

RESUMO

Improvement of insulin sensitivity and lipid and glucose metabolism by coactivation of both nuclear peroxisome proliferator-activated receptor (PPAR)gamma and PPARalpha potentially provides beneficial effects over existing PPARgamma and alpha preferential drugs, respectively, in treatment of type 2 diabetes. We examined the effects of the dual PPARalpha/gamma agonist ragaglitazar on hyperglycemia and whole body insulin sensitivity in early and late diabetes stages in Zucker diabetic fatty (ZDF) rats and compared them with treatment with the PPARgamma preferential agonist rosiglitazone. Despite normalization of hyperglycemia and Hb A(1c) and reduction of plasma triglycerides by both compounds in both prevention and early intervention studies, ragaglitazar treatment resulted in overall reduced circulating insulin and improved insulin sensitivity to a greater extent than after treatment with rosiglitazone. In late-intervention therapy, ragaglitazar reduced Hb A(1c) by 2.3% compared with 1.1% by rosiglitazone. Improvement of insulin sensitivity caused by the dual PPARalpha/gamma agonist ragaglitazar seemed to have beneficial impact over that of the PPARgamma-preferential activator rosiglitazone on glycemic control in frankly diabetic ZDF rats.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Resistência à Insulina , Oxazinas/farmacologia , Fenilpropionatos/farmacologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Tiazóis/farmacologia , Tiazolidinedionas , Fatores de Transcrição/metabolismo , Animais , Composição Corporal , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/prevenção & controle , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Ácidos Graxos não Esterificados/sangue , Técnica Clamp de Glucose , Hemoglobinas Glicadas/análise , Glicogênio/metabolismo , Ilhotas Pancreáticas/citologia , Fígado/metabolismo , Masculino , Ratos , Ratos Zucker , Rosiglitazona
18.
Bioorg Med Chem Lett ; 13(2): 257-60, 2003 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-12482434

RESUMO

Using a known dual PPARalpha/gamma activator (5) as a structural template, SAR evaluations led to the identification of triple PPARalpha/gamma/delta activators (18-20) with equal potency and efficacy on all three receptors. These compounds could become useful tools for studying the combined biological effects of PPARalpha/gamma/delta activation.


Assuntos
Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Fatores de Transcrição/efeitos dos fármacos , Animais , Glicemia/metabolismo , Teste de Tolerância a Glucose , Insulina/sangue , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Receptores Citoplasmáticos e Nucleares/química , Relação Estrutura-Atividade , Fatores de Transcrição/química
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