RESUMO
Compounds that simultaneously activate peroxisome proliferator-activated receptor (PPAR) subtypes α and γ have the potential to effectively treat dyslipidemia and type 2 diabetes (T2D) in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, were expected to be overcome by using additive PPARα activity, leading to dual PPARα/γ agonists with balanced activity for both subtypes. Herein we report the discovery, synthesis, and optimization of a new series of α-ethoxyphenylpropionic acid bearing 5- or 6-substituted indoles. The incorporation of oxime ethers on the carbonyl portion of the benzoyl group can bring the PPARα/γ potency ratio equal to or slightly greater than one, as is the case for compounds 20 c and 21 a. Compound 20 c shows high efficacy in an ob/ob mouse model of T2D and dyslipidemia, similar to that of rosiglitazone and tesaglitazar, but with a significant increase in body weight gain. In contrast, compound 21 a, less potent as a dual PPARα/γ activator than 20 c, showed an interesting pharmacological profile, as it elicits a decrease in body weight relative to reference compounds.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/tratamento farmacológico , Indóis/química , Indóis/uso terapêutico , PPAR alfa/agonistas , PPAR gama/agonistas , Animais , Células COS , Chlorocebus aethiops , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/complicações , Dislipidemias/metabolismo , Indóis/farmacologia , Masculino , Camundongos , Modelos Moleculares , Oximas/química , Oximas/farmacologia , Oximas/uso terapêutico , PPAR alfa/metabolismo , PPAR gama/metabolismo , Propionatos/química , Propionatos/farmacologia , Propionatos/uso terapêutico , Aumento de Peso/efeitos dos fármacosRESUMO
Type-2 diabetes (T2D) is a complex metabolic disease characterized by insulin resistance in the liver and peripheral tissues accompanied by a deficiency in pancreatic beta-cells. Since their discovery, three subtypes of peroxisome proliferator activated receptors have been identified, namely PPARalpha, PPARgamma and PPARbeta/(delta). In this study, we were interested in designing novel PPARgamma selective agonists and/or dual PPARalpha/gamma agonists. Based on the typical topology of synthetic PPAR agonists, we focused our design approach on using 4,4-dimethyl-1,2,3,4-tetrahydroquinoline as a novel cyclic scaffold with oxime and acidic head group structural variations.
Assuntos
Oximas/química , PPAR alfa/agonistas , PPAR gama/agonistas , Quinolinas/síntese química , Quinolinas/farmacologia , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Camundongos , PPAR alfa/metabolismo , PPAR gama/metabolismo , Quinolinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Type-2 diabetes (T2D) is a complex metabolic disease characterized by insulin resistance in the liver and peripheral tissues accompanied by a defect in pancreatic beta-cell. Since their discovery three subtypes of Peroxisomes Proliferators Activated Receptors were identified namely PPARalpha, PPARgamma and PPARbeta/(delta). We were interested in designing novel PPARgamma selective agonists and/or dual PPARalpha/gamma agonists. Based on the typical topology of synthetic PPAR agonists, we focused our design approach on 4,4-dimethyl-1,2,3,4-tetrahydroquinoline as novel cyclic tail.
Assuntos
Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Quinolinas/química , Quinolinas/farmacologia , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of 1,3-dicarbonyl compounds having 2(3H)-benzazolonic heterocycles has been synthesized and tested for PPARgamma agonist activity. SAR were developed and revealed that 6-acyl-2(3H)-benzothiazolone derivatives with 1,3-dicarbonyl group were the most potent. IP administration of compound 22 exhibited comparable levels of glucose and triglyceride correction to PO administration of rosiglitazone in the ob/ob mouse studies.
Assuntos
Compostos Azo/síntese química , Compostos Azo/farmacologia , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , PPAR gama/agonistas , Animais , Compostos Azo/química , Sítios de Ligação , Linhagem Celular , Desenho de Fármacos , Feminino , Compostos Heterocíclicos/química , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , PPAR gama/química , PPAR gama/metabolismo , Relação Estrutura-AtividadeRESUMO
A new class of dual PPARs alpha and gamma agonists was developed. These compounds are structural analogues of the arachidonic acid metabolite, the 8-(S)-HETE. A versatile strategy has been introduced to prepare the target molecules having different carbo- and heterocyclic cores and to modulate the unsaturations on the side chains. Their affinity towards the PPARs alpha and gamma receptors is reported, together with their transactivation percentage. Most of these derivatives have a good activity as dual agonists but the quinoline-derived products appear as the most promising compounds.
