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

• Published in: Journal of medicinal chemistry 2020-12, Vol.63 (24), p.16012-16027
• Main Authors: An, Seungchan, Kim, Gyudong, Kim, Hyun Jin, Ahn, Sungjin, Kim, Hyun Young, Ko, Hyejin, Hyun, Young Eum, Nguyen, Mai, Jeong, Juri, Liu, Zijing, Han, Jinhe, Choi, Hongseok, Yu, Jinha, Kim, Ji Won, Lee, Hyuk Woo, Jacobson, Kenneth A, Cho, Won Jea, Kim, Young-Mi, Kang, Keon Wook, Noh, Minsoo, Jeong, Lak Shin
• Format: Article
• Language: English
• Subjects: Adenosine - chemistry; Adenosine - pharmacology; Adiponectin - metabolism; Animals; Binding Sites; Drug Discovery; Humans; Ligands; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Molecular Dynamics Simulation; Obesity - drug therapy; Obesity - metabolism; Obesity - pathology; PPAR alpha - antagonists & inhibitors; PPAR alpha - metabolism; PPAR gamma - agonists; PPAR gamma - metabolism; Protein Binding; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01874

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.