Non-Peptide GPIIb/IIIa Inhibitors. 20. Centrally Constrained Thienothiophene α-Sulfonamides Are Potent, Long Acting in Vivo Inhibitors of Platelet Aggregation

The synthesis and pharmacology of <BO>4</BO>, a potent thienothiophene non-peptide fibrinogen receptor antagonist, are reported. Compound <BO>4</BO> inhibited the aggregation of human gel-filtered platelets with an IC<INF>50</INF> of 8 nM and demonstrated an 8-fold improvement in affinity for isolated GPIIb/IIIa receptors over analogues possessing an isoindolinone backbone. Flow cytometry studies revealed that the binding of <BO>4</BO> to resting platelets is a diffusion-controlled process (k<INF>on</INF> = 3.3 × 10⁶ M^-1 s^-1) and that <BO>4</BO> binds to dog and human platelets with comparable affinity (K<INF>d</INF> = 0.04 and 0.07 nM, respectively). Ex vivo platelet aggregation in dogs was completely inhibited by an iv dose of 5 mg/kg, and an oral dose of 50−90 mg/kg followed by low daily doses of 10 mg/kg was sufficient to maintain ~80% inhibition of ex vivo platelet aggregation over several days. Inhibition of ADP-induced platelet aggregation in anesthetized dogs at 77 ± 7% resulted in a moderate 2.5-fold increase in bleeding time, while complete inhibition (100%) resulted in an approximately 10-min bleeding time. Additional doses were required to increase the bleeding time to the maximum time allowed in the protocol (15 min), thus indicating a potentially useful and safe separation of efficacy and bleeding time.