RESUMEN
This study sought to determine whether the adipose depot-specific (subcutaneous [SF] vs. visceral [VF]) action of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists on fat deposition extends to the expression of lipoprotein lipase (LPL) and other key adipose lipid metabolism genes, and whether changes in LPL impact triglyceridemia. Rats were fed a standard diet or an obesity-promoting diet for 3 weeks, with or without treatment with COOH, a nonthiazolidinedione PPAR-gamma agonist. Treatment effects were essentially similar in both dietary cohorts. COOH did not affect weight gain, but increased SF (inguinal) fat mass twofold and reduced VF (retroperitoneal) accretion by half. Corresponding depot-specific alterations were observed in mRNA levels of the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD-1) and the thermogenic modulator uncoupling protein 1 (UCP-1). COOH increased brown adipose tissue (BAT) weight and LPL availability by five- to eightfold. In rats refed standard diet after a 24-h fast, COOH reduced the insulin excursion by half. The agonist increased SF LPL activity and mRNA levels, but had no effect on VF LPL. The two- to threefold postprandial increase in plasma triglycerides (TGs) was abrogated in COOH-treated rats, likely in part because of increased LPL in SF and BAT. Thus PPAR-gamma agonist treatment had a powerful, site-specific effect on adipose metabolism and lipid deposition, and greatly impacted the postprandial handling of TG-rich lipoproteins. These depot-specific effects may be mediated by differential regulation of key metabolic genes, including LPL, 11beta-HSD-1, and UCP-1.
Asunto(s)
Tejido Adiposo/fisiología , Regulación de la Expresión Génica/fisiología , Hidroxiesteroide Deshidrogenasas/genética , Lípidos/sangre , Lipoproteína Lipasa/metabolismo , Receptores Citoplasmáticos y Nucleares/fisiología , Factores de Transcripción/fisiología , 11-beta-Hidroxiesteroide Deshidrogenasas , Tejido Adiposo/anatomía & histología , Tejido Adiposo Pardo/anatomía & histología , Animales , Proteínas Portadoras/genética , Cartilla de ADN , Dieta , Grasas de la Dieta , Sacarosa en la Dieta , Ingestión de Energía , Canales Iónicos , Lipoproteína Lipasa/genética , Masculino , Proteínas de la Membrana/genética , Proteínas Mitocondriales , Tamaño de los Órganos , Periodo Posprandial , Ratas , Ratas Sprague-Dawley , Receptores Citoplasmáticos y Nucleares/agonistas , Termogénesis , Factores de Transcripción/agonistas , Proteína Desacopladora 1RESUMEN
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.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hiperlipidemias/tratamiento farmacológico , Hipoglucemiantes/síntesis química , Hipolipemiantes/síntesis química , Isoxazoles/síntesis química , PPAR alfa/agonistas , PPAR gamma/agonistas , Propionatos/síntesis química , Células 3T3-L1 , Animales , Glucemia/efectos de los fármacos , Células COS , Proteínas Portadoras/biosíntesis , Proteínas Portadoras/genética , Chlorocebus aethiops , Colesterol/sangre , Perros , Proteínas de Unión a Ácidos Grasos , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Hipolipemiantes/química , Hipolipemiantes/farmacología , Isoxazoles/química , Isoxazoles/farmacología , Ratones , Ratones Obesos , Propionatos/química , Propionatos/farmacología , ARN Mensajero/biosíntesis , Ensayo de Unión Radioligante , Relación Estructura-Actividad , Activación Transcripcional , Triglicéridos/sangre , Aumento de PesoRESUMEN
The design and synthesis of a novel class of 2,3-dihydrobenzofuran-2-carboxylic acids as highly potent and subtype-selective PPARalpha agonists are reported. Systematic study of structure-activity relationships has identified several key structural elements within this class for maintaining the potency and subtype selectivity. Select compounds were evaluated in animal models of dyslipidemia using Syrian hamsters and male Beagle dogs, and all these compounds displayed excellent cholesterol- and triglyceride-lowering activity at dose levels that were much lower than the marketed weak PPARalpha agonist fenofibrate.
Asunto(s)
Benzofuranos/síntesis química , Ácidos Carboxílicos/síntesis química , Hipolipemiantes/síntesis química , PPAR alfa/agonistas , Animales , Benzofuranos/química , Benzofuranos/farmacología , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Colesterol/sangre , Cricetinae , Perros , Humanos , Hiperlipidemias/tratamiento farmacológico , Hipolipemiantes/química , Hipolipemiantes/farmacología , Técnicas In Vitro , Masculino , Mesocricetus , Conformación Molecular , PPAR alfa/genética , Ensayo de Unión Radioligante , Estereoisomerismo , Relación Estructura-Actividad , Activación Transcripcional , Triglicéridos/sangreRESUMEN
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.
Asunto(s)
Hipoglucemiantes/síntesis química , Hipolipemiantes/síntesis química , PPAR alfa/agonistas , PPAR delta/agonistas , Fenilacetatos/síntesis química , Animales , Cricetinae , Cristalografía por Rayos X , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Perros , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacología , Cinética , Masculino , Mesocricetus , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Modelos Moleculares , Estructura Molecular , Fenilacetatos/química , Fenilacetatos/farmacocinética , Fenilacetatos/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Indoles/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/química , Sulfuros/farmacología , Factores de Transcripción/agonistas , Factores de Transcripción/química , Adipocitos/efectos de los fármacos , Adipocitos/fisiología , Tejido Adiposo/efectos de los fármacos , Animales , Cardiomegalia/inducido químicamente , Células Cultivadas , Regulación de la Expresión Génica/efectos de los fármacos , Hiperglucemia/tratamiento farmacológico , Resistencia a la Insulina , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Conformación Proteica , Aumento de Peso/efectos de los fármacosRESUMEN
The liver X receptors, LXRalpha and LXRbeta, are members of the nuclear receptor superfamily. Originally identified as orphans, both receptor subtypes have since been shown to be activated by naturally occurring oxysterols. LXRalpha knockout mice fail to regulate cyp7a mRNA levels upon cholesterol feeding, implicating the role of this receptor in cholesterol homeostasis. LXR activation also induces the expression of the lipid pump involved in cholesterol efflux, the gene encoding ATP binding cassette protein A1 (ABCA1). Therefore, LXR is believed to be a sensor of cholesterol levels and a potential therapeutic target for atherosclerosis. Here we describe a synthetic molecule named F(3)MethylAA [3-chloro-4-(3-(7-propyl-3-trifluoromethyl-6-(4,5)-isoxazolyl)propylthio)-phenyl acetic acid] that is more potent than 22(R)-hydroxycholesterol in LXR in vitro assays. F(3)MethylAA is capable not only of inducing ABCA1 mRNA levels, but also increasing cholesterol efflux from THP-1 macrophages. In rat hepatocytes, F(3)MethylAA induced cyp7a mRNA, confirming conclusions from the knockout mouse studies. Furthermore, in rat in vivo studies, F(3)MethylAA induced liver cyp7a mRNA and enzyme activity. A critical species difference is also reported in that neither F(3)MethylAA nor 22(R)-hydroxycholesterol induced cyp7a in human primary hepatocytes. However, other LXR target genes, ABCA1, ABCG1, and SREBP1, were regulated.
Asunto(s)
Colesterol 7-alfa-Hidroxilasa/biosíntesis , Colesterol 7-alfa-Hidroxilasa/genética , Regulación Enzimológica de la Expresión Génica/genética , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores de Ácido Retinoico/agonistas , Receptores de Hormona Tiroidea/agonistas , Animales , Apolipoproteína A-I/metabolismo , Northern Blotting , Colesterol/metabolismo , Proteínas de Unión al ADN , Inducción Enzimática/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Humanos , Isoxazoles/farmacología , Receptores X del Hígado , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Receptores Nucleares Huérfanos , Fenilacetatos/farmacología , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Especificidad de la Especie , Activación Transcripcional/genética , Triglicéridos/metabolismoRESUMEN
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.
Asunto(s)
Homeostasis/efectos de los fármacos , Hipolipemiantes/farmacología , Metabolismo de los Lípidos , Éteres Fenílicos/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Tiazolidinedionas/farmacología , Factores de Transcripción/agonistas , Animales , Glucemia/metabolismo , Células COS , Colesterol/biosíntesis , Colesterol/sangre , Cricetinae , Diabetes Mellitus/sangre , Perros , Expresión Génica/efectos de los fármacos , Humanos , Hidroximetilglutaril-CoA Reductasas/efectos de los fármacos , Hidroximetilglutaril-CoA Reductasas/metabolismo , Lípidos/sangre , Hígado/metabolismo , Masculino , Mesocricetus , Ratones , Obesidad/sangre , Éteres Fenílicos/química , ARN Mensajero/metabolismo , Ratas , Ratas Zucker , Tiazolidinedionas/química , Triglicéridos/antagonistas & inhibidores , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
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.
Asunto(s)
Benzopiranos/síntesis química , Cromanos/síntesis química , Hipoglucemiantes/síntesis química , Hipolipemiantes/síntesis química , Éteres Fenílicos/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Animales , Benzopiranos/química , Benzopiranos/farmacocinética , Benzopiranos/farmacología , Cromanos/química , Cromanos/farmacocinética , Cromanos/farmacología , Cricetinae , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Perros , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacología , Macaca mulatta , Masculino , Mesocricetus , Ratones , Éteres Fenílicos/química , Éteres Fenílicos/farmacocinética , Éteres Fenílicos/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Transactivadores/síntesis química , Transactivadores/química , Transactivadores/farmacología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Beginning with a moderately potent PPARgamma agonist 9, a series of potent and highly subtype-selective PPARalpha agonists was identified through a systematic SAR study. Based on the results of the efficacy studies in the hamster and dog models of dyslipidemia and the desired pharmacokinetic data, the optimized compound 39 was selected for further profiling.
Asunto(s)
Diseño de Fármacos , Dislipidemias/tratamiento farmacológico , Hipolipemiantes/síntesis química , PPAR alfa/agonistas , Animales , Cricetinae , Perros , Haplorrinos , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacología , Estructura Molecular , PPAR alfa/genética , Ratas , Relación Estructura-Actividad , Activación TranscripcionalRESUMEN
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.
Asunto(s)
Mediadores de Inflamación/metabolismo , PPAR gamma/agonistas , Animales , Benzoatos/síntesis química , Benzoatos/farmacología , Benzoatos/uso terapéutico , Diabetes Mellitus/tratamiento farmacológico , Modelos Animales de Enfermedad , Humanos , Indoles/síntesis química , Indoles/farmacología , Indoles/uso terapéutico , Ligandos , Estructura Molecular , PPAR gamma/metabolismoRESUMEN
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.
Asunto(s)
Ácidos Carboxílicos/farmacología , Cromanos/farmacología , Hipolipemiantes/farmacología , PPAR alfa/agonistas , Animales , Ácidos Carboxílicos/administración & dosificación , Ácidos Carboxílicos/síntesis química , Cromanos/administración & dosificación , Cromanos/síntesis química , Cricetinae , Perros , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Hipolipemiantes/administración & dosificación , Hipolipemiantes/síntesis química , Macaca mulatta , Masculino , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie , Relación Estructura-ActividadRESUMEN
A series of metabolically robust N-benzyl-indole selective PPARgamma modulators with either a 3-benzoyl or 3-benzisoxazoyl moiety have been identified. In vitro, these compounds are partial agonists and exhibit reduced adipogenesis in human adipocytes. In vivo, these SPPARgammaMs result in potent glucose lowering in db/db mice and attenuate increases in heart weight and brown adipose tissue that is typically observed in rats upon treatment with PPARgamma full agonists.
Asunto(s)
Indoles/farmacología , PPAR gamma/efectos de los fármacos , Animales , Área Bajo la Curva , Glucemia/metabolismo , Humanos , Indoles/química , Indoles/farmacocinética , Ratones , RatasRESUMEN
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.
Asunto(s)
Isoxazoles/química , Isoxazoles/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Tiazolidinedionas , Factores de Transcripción/agonistas , Administración Oral , Animales , Disponibilidad Biológica , Células COS , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Modelos Animales de Enfermedad , Humanos , Isoxazoles/farmacocinética , Ratones , Ratones Mutantes , Proteínas Nucleares/agonistas , Proteínas Nucleares/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Rosiglitazona , Tiazoles/farmacocinética , Tiazoles/farmacología , Factores de Transcripción/metabolismoRESUMEN
Increased levels of triglyceride-rich lipoproteins provoke lipid accumulation in the artery wall, triggering early inflammatory responses central to atherosclerosis like endothelial adhesion molecule expression. The endogenous mechanisms limiting such reactions remain poorly defined. Lipoprotein lipase (LPL) plays a central role in lipid metabolism by hydrolyzing triglyceride rich lipoproteins and releasing fatty acids. We found that LPL treatment reversed tumor necrosis factor alpha and very low-density lipoprotein (VLDL)-stimulated endothelial vascular cell adhesion molecule 1 (VCAM1) induction and VCAM1 promoter responses, thus recapitulating effects reported with synthetic peroxisome proliferator-activated receptor (PPAR) agonists. In fact, these LPL effects on VCAM1 were absent in endothelial cells isolated from PPAR alpha-deficient mice. This finding suggests a novel antiinflammatory role for LPL. Further studies reveal specificity for PPAR activation through lipolysis in regards to lipoprotein substrate (VLDL >> LDL > HDL), PPAR isoform (PPAR alpha >> PPAR delta > PPAR gamma), and among fatty acid-releasing lipases. These PPAR responses required intact LPL catalytic activity. In vivo, transgenic mice overexpressing LPL had increased peroxisome proliferation, but not in the genetic absence of PPAR alpha. Although human plasma possesses minimal PPAR alpha activation despite containing abundant free fatty acids, marked PPAR alpha activation is seen with human plasma after LPL is added in vitro or systemically released in vivo. These data suggest a previously uncharacterized pathway in which the key lipolytic enzyme LPL can act on circulating lipoproteins to generate PPAR alpha ligands, providing a potentially important link between lipoprotein metabolism and distal PPAR alpha transcriptional effects.
Asunto(s)
Antiinflamatorios/farmacología , Lipoproteína Lipasa/fisiología , Lipoproteínas/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/metabolismo , Triglicéridos/metabolismo , Animales , Northern Blotting , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ácidos Grasos/metabolismo , Humanos , Inmunohistoquímica , Ligandos , Metabolismo de los Lípidos , Lipólisis , Lipoproteínas VLDL/metabolismo , Ratones , Ratones Transgénicos , Microscopía Fluorescente , Modelos Biológicos , Isoformas de Proteínas , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Transcripción Genética , Transfección , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
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.
Asunto(s)
Hipoglucemiantes/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Tiazolidinedionas/síntesis química , Factores de Transcripción/agonistas , Administración Oral , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Modelos Animales de Enfermedad , Hiperglucemia/tratamiento farmacológico , Hipertrigliceridemia/tratamiento farmacológico , Hipoglucemiantes/farmacología , Ratones , Receptores Citoplasmáticos y Nucleares/metabolismo , Rosiglitazona , Relación Estructura-Actividad , Tiazolidinedionas/farmacología , Factores de Transcripción/metabolismoRESUMEN
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.
Asunto(s)
Ácidos Mandélicos/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Animales , Ácidos Mandélicos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Ratas , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/metabolismoRESUMEN
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.
Asunto(s)
Hipoglucemiantes/síntesis química , Receptores Citoplasmáticos y Nucleares/agonistas , Tiazolidinedionas/síntesis química , Tiazolidinedionas/farmacocinética , Factores de Transcripción/agonistas , Animales , Glucemia/efectos de los fármacos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Modelos Animales de Enfermedad , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Concentración 50 Inhibidora , Ratones , Relación Estructura-Actividad , Tiazolidinedionas/farmacologíaRESUMEN
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.
Asunto(s)
Hipoglucemiantes/farmacología , Oxazoles/farmacología , Receptores Citoplasmáticos y Nucleares/agonistas , Factores de Transcripción/agonistas , Administración Oral , Hipoglucemiantes/química , Hipoglucemiantes/farmacocinética , Oxazoles/química , Oxazoles/farmacocinética , Relación Estructura-ActividadRESUMEN
The LXR nuclear receptors are intracellular sensors of cholesterol excess and are activated by various oxysterols. LXRs have been shown to regulate multiple genes of lipid metabolism, including ABCA1 (formerly known as ABC1). ABCA1 is a lipid pump that effluxes cholesterol and phospholipid out of cells. ABCA1 deficiency causes extremely low high density lipoprotein (HDL) levels, demonstrating the importance of ABCA1 in the formation of HDL. The present work shows that the acetyl-podocarpic dimer (APD) is a potent, selective agonist for both LXRalpha (NR1H3) and LXRbeta (NR1H2). In transient transactivation assays, APD was approximately 1000-fold more potent, and yielded approximately 6-fold greater maximal stimulation, than the widely used LXR agonist 22-(R)-hydroxycholesterol. APD induced ABCA1 mRNA levels, and increased efflux of both cholesterol and phospholipid, from multiple cell types. Gas chromatography-mass spectrometry measurements demonstrated that APD stimulated efflux of endogenous cholesterol, eliminating any possible artifacts of cholesterol labeling. For both mRNA induction and stimulation of cholesterol efflux, APD was found to be more effective than was cholesterol loading. Taken together, these data show that APD is a more effective LXR agonist than endogenous oxysterols. LXR agonists may therefore be useful for the prevention and treatment of atherosclerosis, especially in the context of low HDL levels.