Regio- and Stereoselective Ribose Modification in Truncated 2,8-Disubstituted Adenosine Scaffold to Develop Highly...

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Molecular Biology

Background:

• Adenosine receptors, particularly hA_2AAR, are key targets for immune modulation.
• Previous studies utilized molecular dynamics and SAR to guide the design of hA_2AAR ligands.

Purpose of the Study:

• To synthesize and evaluate novel ribose derivatives of hA_2AAR ligands.
• To enhance potency and selectivity for hA_2AAR through modifications of the ribose moiety.
• To identify potential orally available immune checkpoint inhibitors.

Main Methods:

• Regio- and stereoselective synthesis of diol-, deoxy-, fluoro-, and methoxy-ribose derivatives.
• Structure-activity relationship (SAR) analysis for hA_2AAR and hA₃AR binding.
• In vitro potency and functional efficacy assays.
• Pharmacokinetic profiling and in vivo efficacy studies.

Main Results:

• SAR indicated a preference for at least one hydroxyl group at R² or R⁴ for hA_2AAR binding.
• Alterations in ribose hydroxyl groups influenced selectivity, with hA₃AR favoring diol derivatives.
• The deoxy derivative 4d exhibited exceptional in vitro potency (K_i,hA2A = 0.36 ± 0.05 nM) and functional efficacy at hA_2AAR.
• Derivative 4d demonstrated favorable pharmacokinetics and in vivo efficacy.

Conclusions:

• Modification of the ribose moiety is a viable strategy to optimize hA_2AAR ligand properties.
• The deoxy derivative 4d is a potent and effective hA_2AAR ligand with potential as an orally administered immune checkpoint inhibitor.