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

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dc.contributor.authorDutra, Luiz A. [UNESP]
dc.contributor.authorLacerda, Mariella G.
dc.contributor.authorDestro Inácio, Maiara [UNESP]
dc.contributor.authorMartins, Johnny W.L. [UNESP]
dc.contributor.authorLopes Silva, Ana C. [UNESP]
dc.contributor.authorBento da Silva, Patricia [UNESP]
dc.contributor.authorChorilli, Marlus [UNESP]
dc.contributor.authorAmato, Angélica A.
dc.contributor.authorBaviera, Amanda M. [UNESP]
dc.contributor.authorPassarelli, Marisa
dc.contributor.authorGuido, Rafael V.C.
dc.contributor.authorDos Santos, Jean L. [UNESP]
dc.contributor.institutionUniversidade Estadual Paulista (UNESP)
dc.contributor.institutionCampos Univ. Darcy Ribeiro s/n – Asa Norte
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionRua Vergueiro 235/249 – Liberdade
dc.date.accessioned2022-04-29T08:46:31Z
dc.date.available2022-04-29T08:46:31Z
dc.date.issued2022-03-01
dc.description.abstractPeroxisome 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 PPARα/γ 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 14C-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.en
dc.description.affiliationSchool of Pharmaceutical Science São Paulo State University (UNESP) Rodovia Araraquara Jaú Km 01 – s/n
dc.description.affiliationLaboratory of Molecular Pharmacology Faculty of Health Sciences University of Brasilia Campos Univ. Darcy Ribeiro s/n – Asa Norte
dc.description.affiliationLaboratório de Lípides (LIM 10) Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo 455 – Cerqueira César
dc.description.affiliationPrograma de Pós-Graduação em Medicina da Universidade Nove de Julho – UNINOVE Rua Vergueiro 235/249 – Liberdade
dc.description.affiliationSão Carlos Institute of Physics University of Sao Paulo, Av. João Dagnone 1100 – São Carlos-SP
dc.description.affiliationUnespSchool of Pharmaceutical Science São Paulo State University (UNESP) Rodovia Araraquara Jaú Km 01 – s/n
dc.identifierhttp://dx.doi.org/10.1016/j.bioorg.2022.105600
dc.identifier.citationBioorganic Chemistry, v. 120.
dc.identifier.doi10.1016/j.bioorg.2022.105600
dc.identifier.issn1090-2120
dc.identifier.issn0045-2068
dc.identifier.scopus2-s2.0-85123180042
dc.identifier.urihttp://hdl.handle.net/11449/231602
dc.language.isoeng
dc.relation.ispartofBioorganic Chemistry
dc.sourceScopus
dc.subjectAdipogenesis
dc.subjectGlucose homeostasis
dc.subjectHDL-C
dc.subjectPON1
dc.subjectPPARs
dc.subjectStilbene
dc.titleDiscovery of (E)-4-styrylphenoxy-propanamide: A dual PPARα/γ partial agonist that regulates high-density lipoprotein-cholesterol levels, modulates adipogenesis, and improves glucose tolerance in diet-induced obese miceen
dc.typeArtigo

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