A novel class of ion displacement ligands as antagonists of the αIIbβ3 receptor that limit conformational reorganization of the receptor

Abstract

A collection of αIIbβ3 integrin receptor antagonists possessing a unique MIDAS metal ion displacement mechanism of action is presented. Insight into these agents’ structure-activity relationships, binding modality, and pharmacokinetic and pharmacodynamic profiles highlight the potential of these small molecule ion displacement ligands as attractive candidates for clinical development.

Ruc-4

“…As a result, we synthesized congeners of RUC-2 and identified RUC-4, which is slightly more potent than RUC-2 and more than 500-fold more soluble. 35 We now report on RUC-4’s properties with regard to specificity, priming, and ability to induce conformational changes in the β3 subunit. We also provide data on its mechanism of action, pharmacokinetics and pharmacodynamics in mice and non-human primates, and antithrombotic properties in mouse models that use both mouse and human platelets.…”

The platelet: life on the razor's edge between hemorrhage and thrombosis

“…To address the unmet medical need for effective prehospital therapy of STEMI we first performed a high throughput screen of more than 33,000 compounds and identified one (RUC‐1) that inhibited αIIbβ3‐mediated adhesion of human platelets to fibrinogen . We went on to make derivatives of RUC‐1 and found RUC‐2, which is approximately 100‐fold more potent and has a unique mechanism of action that involves competing for a carboxyl group on glutamic acid residue in the β3 subunit (E220) that is crucial for binding the divalent cation Mg 2+ in a specialized domain termed the metal ion–dependent adhesion site (MIDAS) . Ligands, including fibrinogen and von Willebrand factor, bind to αIIbβ3 in part by having an aspartic acid carboxyl group oxygen coordinate the MIDAS Mg 2+ .…”

“…What RUC‐2 lacks, however, is the high aqueous solubility required for delivery by autoinjector since an adult dose needs to be contained in no more than approximately 1 mL. As a result, we made modifications in RUC‐2 and produced RUC‐4, which differs only in substituting a nitrogen for a carbon in one of the phenyl rings, but is much more soluble . RUC‐4 has many of the same features as RUC‐2, and in addition it is rapidly effective in inhibiting platelets after IM administration in nonhuman primates.…”

Emergence of Small-Molecule Non-RGD-Mimetic Inhibitors for RGD Integrins

“…54 This more potent analogue was soaked into crystals of the α IIb β 3 headpiece, but no density for the metal ion at the MIDAS was observed (PDB 3T3M, Figure 6). 54 It was noted that 9 had the same binding interactions as 8 but with additional interactions in the β 3 βI domain.…”

“…54 This more potent analogue was soaked into crystals of the α IIb β 3 headpiece, but no density for the metal ion at the MIDAS was observed (PDB 3T3M, Figure 6). 54 It was noted that 9 had the same binding interactions as 8 but with additional interactions in the β 3 βI domain. The primary amine of 9 was discovered to compete with the Mg 2+ for interactions with the carboxyl oxygen of Glu220; thus, in high enough concentration, 9 displaced the metal ion of the MIDAS, explaining its absence from the crystal structure.…”