Exploring the Effect of Halogenation in a Series of Potent and Selective A 2B Adenosine Receptor Antagonists.

The modulation of the A adenosine receptor is a promising strategy in cancer (immuno) therapy, with AAR antagonists emerging as immune checkpoint inhibitors. Herein, we report a systematic assessment of the impact of (di- and mono-)halogenation at positions 7 and/or 8 on both AAR affinity and pharmacokinetic properties of a collection of AAR antagonists and its study with structure-based free energy perturbation simulations. Monohalogenation at position 8 produced potent AAR ligands irrespective of the nature of the halogen. In contrast, halogenation at position 7 and dihalogenation produced a halogen-size-dependent decay in affinity. Eight novel AAR ligands exhibited remarkable affinity ( < 10 nM), exquisite subtype selectivity, and enantioselective recognition, with some eutomers eliciting sub-nanomolar affinity. The pharmacokinetic profile of representative derivatives showed enhanced solubility and microsomal stability. Finally, two compounds showed the capacity of reversing the antiproliferative effect of adenosine in activated primary human peripheral blood mononuclear cells.