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

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posted on 03.11.2005 by Heiko Ullmann, Sabine Meis, Darunee Hongwiset, Claudia Marzian, Michael Wiese, Peter Nickel, Didier Communi, Jean-Marie Boeynaems, Christian Wolf, Ralf Hausmann, Günther Schmalzing, Matthias U. Kassack
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, pKi:  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.

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