NONPEPTIDE FIBRINOGEN RECEPTOR ANTAGONISTS .7. DESIGN AND SYNTHESIS OF A POTENT, ORALLY-ACTIVE FIBRINOGEN RECEPTOR ANTAGONIST

The design, synthesis, and pharmacological evaluation of L-734,217, a potent, low-molecular weight, orally active fibrinogen receptor antago nist, is reported. A strategy for producing low-molecular weight inhib itors from the peptide c-[(Ac)CRGDC] A, previously reported from these laboratories, is outlined. This strategy combines a retrodesign analy sis of the conformationally defined cyclic peptide A with stereochemic al information present in the arginine-glycine-aspartic acid (RGD) tri peptide sequence, culminating with the discovery of L-734,217. L-734,2 17 inhibited the aggregation of human, dog, and chimpanzee platelets a t concentrations below 100 nM and was found to be > 15000-fold less ef fective at inhibiting the attachment of human umbilical vein endotheli al cells to fibrinogen, fibronectin, and vitronectin than it was at in hibiting the aggregation of platelets. L-734,217 showed significant ex vivo antiplatelet activity following oral administration in dogs and chimpanzees at doses of 1.0 and 2.0 mg/kg, respectively, and has been selected as a clinical candidate for development as an antithrombotic agent.