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

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)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 A 3 AR 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.

International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update

“…Further potent A 3 AR antagonists, including MRE3008-F20 (31) ( Baraldi et al, 2012 ; Borea et al, 2015 ), PSB-10 (32) ( Ozola et al, 2003 ; Alnouri et al, 2015 ), and VUF5574 (33) ( van Muijlwijk-Koezen et al, 2000 ) are highly potent and selective in human but virtually inactive at rodent A 3 ARs (see Table 2 ). As species differences are more pronounced for A 3 AR antagonists than for agonists, most of which are derivatives or analogs of adenosine, compounds with a truncated, furanyl, or carbocyclic moiety in place of the ribose ring of adenosine were investigated and optimized ( Jeong et al, 2007 ; Lee et al, 2010 ; Nayak et al, 2014 ; An et al, 2020 ). Such adenosine analogs show reduced intrinsic activity or even block the receptors.…”

Stereoselective Synthesis of (S)- and (N)-Cyclopropyl-Fused Carbocyclic Nucleosides Using Stereoselective Cyclopropanation

“…We recently reported that novel peroxisome proliferator-activated receptor (PPAR) γ/δ dual modulators ( 1 and 2 ), which function as both PPARγ partial agonists and PPARδ antagonists, have therapeutic potential against cancer and metabolic diseases associated with hypoadiponectinemia. Those 1′-homologated nucleosides abolished typical binding to adenosine receptors and polymerases, making them inactive . In view of medicinal chemistry, this finding looks important in that it opened up a novel scaffold for the development of pure PPAR modulators.…”

“…Those 1′-homologated nucleosides abolished typical binding to adenosine receptors and polymerases, making them inactive. 4 In view of medicinal chemistry, this finding looks important in that it opened up a novel scaffold for the development of pure PPAR modulators.…”

“…2, 84.6, 81.4, 65.1, 35.7, 33.1, 27.6, 25.0, 22.4, 15.2; HRMS (CI) m/z: [M + H] + Calcd for C 10 H 17 O 3 185.1178;Found 185.1177. ((3aS,3bS,4aS,5aR)-2,2-Dimethyltetrahydrocyclopropa[3,4]cyclopenta [1,2-d][1,3]dioxol-3b(3aH)-yl)methanol (5α) and ((3aS,3bR,4aR,4] 1, entry 1). To a stirred solution of diethylzinc (Et 2 Zn, 1.0 M in hexanes, 2.6 mL, 2.6 mmol, 2.0 equiv) in CH 2 Cl 2 (4 mL) was added diiodomethane (CH 2 I 2 , 0.4 mL, 5.29 mmol, 4.0 equiv) carefully at 0 °C.…”

“…6-Chloro-9-(((3aS,3bS,4aS,5aR)-2,2-dimethyltetrahydrocyclopropa [3,4] and 2,3bS,4aS,4]cyclopenta [1,2-d][1,3]dioxol-3b(3aH)yl)methyl)-9H-purine (20b). To a stirred solution of 5α (215 mg for 20a or 278 mg for 20b, 1.0 equiv) in THF (15 mL) were added triphenylphosphine (PPh 3 , 611 mg for 20a or 796 mg for 20b, 2.0 equiv), and 6-chloropurine (360 mg, 2.0 equiv for 20a) or 2,6dichloropurine (569 mg, 2.0 equiv for 20b) at 23 o C. The reaction mixture was cooled to 0 °C, and diisopropyl azodicarboxylate (DIAD, 0.46 mL for 20a or 0.59 mL for 20b, 2.0 equiv) was added dropwise.…”