Medicinal Chemistry and Drug Design

Biography

Biography: Letizia Giampietro

Abstract

Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear hormone receptors expressed especially in metabolically active tissues. Three different isoforms namely PPAR, PPAR and PPAR are identified; they play important roles in lipid and glucose homeostasis. The research of dual PPAR/ and pan PPAR α/γ/δ agonists could be useful to treat simultaneously dyslipidemia and type 2 diabetes mellitus, reducing side effects of selective PPAR agonists.¹ Fibrates active as PPAR agonists have, as typical pharmacophore, a carboxylic acid head and an aromatic ring with or without different spacers. Based on this pharmacophore, in the past, we reported synthesis and biological evaluation of various fibrate analogues. These compounds showed good activation of PPARs.^2,3 In particular, a dual PPARα/γ agonist, named GL479 (αEC₅₀=0.6 M and γEC₅₀=1.4 M), was identified (Figure 1; R = H; X = O; Y = CH₂).⁴ This compound was crystallized with PPARα and PPARγ in order to explain its particular binding mode with the receptors ligand binding domain.⁵ In view of these results, and to gain more insight on the structure-activity relationships, we synthesized new GL479 analogues with the oxygen of the linker in para to the 2-methyl-2-phenoxypropanoic group and with different substituents in para to the phenyldiazenyl moiety (Figure 1). All compounds were tested in a cell-based transactivation assay to evaluate the agonist activity toward the human PPARα, -γ and -β/δ. The obtained results led to the identification of some fibrate derivatives with promising activity on the three PPAR isoforms.  In particular, a docking study of the best candidate clarified the possible binding modes with PPARα, -γ and -β/δ. Moreover, in vitro and ex vivo studies on tested compounds allowed us to discover an interesting lead for the development of a new class of PPAR agonists exploitable for therapy of metabolic syndrome.