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

Author(s):Show less -

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.

• Document type: Journal article
• Source: BIOORGANIC CHEMISTRY; v. 120, p. 12-pg., 2022-01-22.

Abstract

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)

• FAPESP's process: 14/03945-9 - Design, synthesis and pharmacological evaluation of new resveratrol derivatives useful for dyslipidemia treatment
• Grantee: Luiz Antonio Dutra
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 15/21271-8 - Pharmacological evaluation of resveratrol derivatives as dual bromodomain/PPARs inhibitors to treat dyslipidemia
• Grantee: Luiz Antonio Dutra
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate