RESUMO
We have discovered and demonstrated the in vitro and in vivo PPARδ-selective activity of novel Y-shaped agonists. These compounds activated hPPARδ with EC(50) values between 1 and 523 nM. Surprisingly, compounds 10a, 11d, 11e and 11f were the most potent and most selective hPPARδ agonists with 10(4)-fold selectivity over the other two subtypes, namely, hPPARα and hPPARγ. The PPARδ ligands 10a, 11e and 11f showed good bioavailability and in vivo efficacy.
Assuntos
Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Desenho de Fármacos , PPAR delta/agonistas , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Técnicas de Química Sintética , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Modelos Moleculares , Obesidade/tratamento farmacológico , Obesidade/etiologia , PPAR delta/química , Conformação ProteicaRESUMO
Three new scalarane-based sesterterpenes, 1- 3, were isolated from a marine sponge of the genus Spongia, and their chemical structures were elucidated by analysis of HRMS and 2-D NMR spectra. The isolated compounds 1 and 3 showed inhibition against the farnesoid X-activated receptor (FXR) with IC50 values of 2.4 and 24 microM, respectively. In particular, compound 3 directly inhibited the interaction between FXR and a coactivator peptide (SRC-1) as determined by surface plasmon resonance (SPR) spectroscopy.
