Discovery of Isoquinolinoquinazolinones as a Novel Class of Potent PPARÎ 3 Antagonists with Anti-adipogenic Effects

Abstract

Conformational change in helix 12 can alter ligand-induced PPARλ 3 activity; based on this reason, isoquinolinoquinazolinones, structural homologs of berberine, were designed and synthesized as PPARÎ 3 antagonists. Computational docking and mutational study indicated that isoquinolinoquinazolinones form hydrogen bonds with the Cys285 and Arg288 residues of PPARλ 3. Furthermore, SPR results demonstrated strong binding affinity of isoquinolinoquinazolinones towards PPARλ 3. Additionally, biological assays showed that this new series of PPARλ 3 antagonists more strongly inhibit adipocyte differentiation and PPARÎ 32-induced transcriptional activity than GW9662.