Discovery and Structure-Activity Relationships of Novel Template, Truncated 1′-Homologated Adenosine Derivatives as Pure Dual PPARγ/δModulators

Abstract

Following our report that A(3) adenosine receptor (AR) antagonist 1 exhibited a polypharmacological profile as a dual modulator of peroxisome proliferator-activated receptor (PPAR)gamma/delta, we discovered a new template, 1'-homologated adenosine analogues 4a-4t, as dual PPARy/delta modulators without AR binding. Removal of binding affinity to A(3)AR was achieved by 1'-homologation, and PPAR gamma/delta dual modulation was derived from the structural similarity between the target nucleosides and PPAR modulator drug, rosiglitazone. All the final nucleosides were devoid of AR-binding affinity and exhibited high binding affinities to PPAR gamma/delta but lacked PPAR alpha binding. 2-Cl derivatives exhibited dual receptor-binding affinity to PPAR gamma/delta, which was absent for the corresponding 2-H derivatives. 2-Propynyl substitution prevented PPAR delta-binding affinity but preserved PPAR gamma affinity, indicating that the C2 position defines a pharmacophore for selective PPAR gamma ligand designs. PPAR gamma/delta dual modulators functioning as both PPAR gamma partial agonists and PPAR delta antagonists promoted adiponectin production, potential against hypoadiponectinemia-associated cancer and metabolic diseases.