Non-peptide GPIIb IIIa inhibitors. 20. Centrally constrained thienothiophene alpha-sulfonamides are potent, long acting in vivo inhibitors of platelet aggregation

The synthesis and pharmacology of 4, a potent thienothiophene non-peptide f ibrinogen receptor antagonist, are reported. Compound 4 inhibited the aggre gation of human gel-filtered platelets with an IC50 of 8 nM and demonstrate d an 8-fold improvement in affinity for isolated GPIIb/IIIa receptors over analogues possessing an isoindolinone backbone. Flow cytometry studies reve aled that the binding of 4 to resting platelets is a diffusion-controlled p rocess (k(on) = 3.3 x 10(6) M-1 s(-1)) and that 4 binds to dog and human pl atelets with comparable affinity (K-d = 0.04 and 0.07 nM, respectively). Ex vivo platelet aggregation in dogs was completely inhibited by an iv dose o f 5 mg/kg, and an oral dose of 50-90 mg/kg followed by low daily doses of 1 0 mg/kg was sufficient to maintain similar to 80% inhibition of ex vivo pla telet aggregation over several days. Inhibition of ADP-induced platelet agg regation 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 incre ase the bleeding time to the maximum time allowed in the protocol (15 min), thus indicating a potentially useful and safe separation of efficacy and b leeding time.