Discovery and Structure–Activity Relationships of Novel Template, Truncated 1′-Homologated Adenosine Derivatives as Pure Dual PPARγ/δ Modulators
Seungchan An, Gyudong Kim, Hyun‐Jin Kim, Sungjin Ahn, Ho Kim, Hyejin Ko, Young Eum Hyun, Mai Nguyen, Juri Jeong, Zijing Liu, Jinhe Han, Hongseok Choi, Jinha Yu, Ji Won Kim, Hyuk Woo Lee, Kenneth A. Jacobson, Won Jea Cho, Young‐Mi Kim, Keon Wook Kang, Minsoo Noh, Lak Shin Jeong
Abstract
Following our report that A3 adenosine receptor (AR) antagonist 1 exhibited a polypharmacological profile as a dual modulator of peroxisome proliferator-activated receptor (PPAR)γ/δ, we discovered a new template, 1′-homologated adenosine analogues 4a–4t, as dual PPARγ/δ modulators without AR binding. Removal of binding affinity to A3AR was achieved by 1′-homologation, and PPARγ/δ 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 PPARγ/δ but lacked PPARα binding. 2-Cl derivatives exhibited dual receptor-binding affinity to PPARγ/δ, which was absent for the corresponding 2-H derivatives. 2-Propynyl substitution prevented PPARδ-binding affinity but preserved PPARγ affinity, indicating that the C2 position defines a pharmacophore for selective PPARγ ligand designs. PPARγ/δ dual modulators functioning as both PPARγ partial agonists and PPARδ antagonists promoted adiponectin production, suggesting their therapeutic potential against hypoadiponectinemia-associated cancer and metabolic diseases.