Synthesis and Structure−Activity Relationships of Suramin-Derived P2Y₁₁ Receptor Antagonists with Nanomolar Potency

Selective and potent P2Y₁₁ receptor antagonists have yet to be developed, thus impeding an evaluation of this G protein-coupled receptor mainly expressed on immune cells. Taking suramin with moderate inhibitory potency as a template, 18 ureas with variations of the methyl groups of suramin and their precursors were functionally tested at P2Y₁₁, P2Y₁, and P2Y₂ receptors. Fluorine substitution of the methyl groups of suramin led to the first nanomolar P2Y₁₁ antagonist (8f, NF157, pK_i:  7.35). For selectivity, 8f was also tested at various P2X receptors. 8f displayed selectivity for P2Y₁₁ over P2Y₁ (>650-fold), P2Y₂ (>650-fold), P2X₂ (3-fold), P2X₃ (8-fold), P2X₄ (>22-fold), and P2X₇ (>67-fold) but no selectivity over P2X₁. QSAR studies confirm that residues with favored resonance and size parameters in the aromatic linker region can indeed lead to an increased potency as is the case for 8f. A symmetric structure linking two anionic clusters seems to be required for bioactivity. 8f may be helpful for studies evaluating the physiological role of P2Y₁₁ receptors.