Non-Peptide RGD Surrogates Which Mimic a Gly-Asp β-Turn: Potent Antagonists of Platelet Glycoprotein IIb−IIIa

Cyclic heptapeptide 1, which contains an Arg-Gly-Asp sequence, has good affinity for the platelet receptor GPIIb−IIIa and was chosen for study by 1H NMR techniques. The key RGD sequence of this molecule was found to reside in a conformationally defined type II‘ Gly-Asp β-turn, and this information was used in the design of simple non-peptide RGD mimics. Disubstituted isoquinolones, bearing an acidic side chain at position 2 and a basic side chain at position 6, were prepared and were found to have modest affinity for GPIIb−IIIa. Systematic modification of the basic residue contained in these molecules yielded compounds with high affinity for GPIIb−IIIa.