Discovery of (E)-4-styrylphenoxy-propanamide: A dual PPAR alpha/gamma partial agonist that regulates high-density lipoprotein-cholesterol levels, modulates adipogenesis, and improves glucose tolerance in diet-induced obese mice

Autor(es):Mostrar menos -

Dutra, Luiz A. ; Lacerda, Mariella G. ; Inacio, Maiara Destro ; Martins, Johnny W. L. ; Lopes Silva, Ana C. ; da Silva, Patricia Bento ; Chorilli, Marlus ; Amato, Angelica A. ; Baviera, Amanda M. ; Passarelli, Marisa ; Guido, Rafael V. C. ; Dos Santos, Jean L.

• Tipo de documento: Artigo Científico
• Fonte: BIOORGANIC CHEMISTRY; v. 120, p. 12-pg., 2022-01-22.

Resumo

Peroxisome proliferator-activated receptors are promising therapeutic targets for metabolic diseases, including obesity, diabetes, and dyslipidemia. This study describes the design, synthesis and pharmacological evaluation of stilbene-based compounds as dual PPAR alpha/gamma partial agonists with potency in the nanomolar range. In vitro and in vivo assays revealed that the lead compound (E)-4-styrylphenoxy-propanamide (5b) removed C-14-cholesterol from the foam cells through apolipoprotein A-I and High-Density Lipoprotein-2. In the high-fat diet-induced obesity mouse model, the oral administration of compound 5b increased HDL levels, paraoxonase-1 activity, and insulin sensitivity, and decreased glucose levels. Moreover, the adipogenesis pathway and triglyceride accumulation slightly changed in the adipocyte cells upon treatment with compound 5b, without affecting the body weight and adipose tissue in obese mice. Compound 5b did not affect the plasma levels of hepatic and renal injury biomarkers. Thus, stilbene-based compound 5b is a promising prototype for developing novel candidates to treat dyslipidemia and diabetes. (AU)

• Processo FAPESP: 14/03945-9 - Planejamento, síntese e avaliação farmacológica de novos compostos derivados de resveratrol úteis ao tratamento da dislipidemia
• Beneficiário: Luiz Antonio Dutra
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
• Beneficiário: Glaucius Oliva
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 15/21271-8 - Avaliação farmacológica de derivados de resveratrol como inibidores duplos de Bromodomain/PPAR para o tratamento da dislipidemia
• Beneficiário: Luiz Antonio Dutra
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado