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

Seungchan An, Gyudong Kim, Hyun Jin Kim, Sungjin Ahn, Hyun Young 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 NohLak Shin Jeong

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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/δmodulators without AR binding. Removal of binding affinity to A3AR was achieved by 1′-homologation, and PPARγ/δdual 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/δbut 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 PPARγaffinity, indicating that the C2 position defines a pharmacophore for selective PPARγligand designs. PPARγ/δdual modulators functioning as both PPARγpartial agonists and PPARδantagonists promoted adiponectin production, suggesting their therapeutic potential against hypoadiponectinemia-associated cancer and metabolic diseases.

Original languageEnglish
Pages (from-to)16012-16027
Number of pages16
JournalJournal of Medicinal Chemistry
Volume63
Issue number24
DOIs
StatePublished - 24 Dec 2020

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