Antithrombotic activity of BMY-43351, a new imidazoquinoline with enhanced aqueous solubility

Abstract

BMY-43351 is a new broad-spectrum inhibitor of platelet aggregation with greater aqueous solubility than earlier analogs from the imidazoquinoline series. This report compares the antithrombotic activity of BMY-43351 to that of two other imidazoquinolines: BMY-20844, a simply-substituted compound, and BMY-21638, a more potent ether-linked side chain analog. All of these compounds act, at least in part, via inhibition of platelet low-Km cyclic AMP phosphodiesterase. Antithrombotic activity was assessed in the rabbit ear chamber-biolaser preparation, an animal model of small vessel thrombosis, and in the canine coronary artery stenosis-occlusion model of large vessel thrombosis. BMY-43351 was found to be remarkably potent in the biolaser model, with an EDso of 0.074 mg/kg p.o. In comparison, compounds such as aspirin, ticlopidine, sulfinpyrazone, and dipyridamole demonstrate little or no activity at much higher doses, (eg. 100 mg/kg p.o.). Other inhibitors of platelet low Km cyclic AMP phosphodiesterase are active but substantially weaker than BMY-43351. Similarly, in the coronary artery stenosis-occlusion model, BMY-43351 demonstrated impressive activity, significantly inhibiting arterial thrombosis at intraduodenal doses as low as 1 micrograms/kg. The potential use of BMY-43351 as adjunct therapy in thrombolysis was suggested in a series of experiments where this drug was used in combination with a thrombolytic regimen of stretokinase plus heparin. In this experimental setting, time to reperfusion was reduced from 42 +/- 5 minutes to 11 +/- 5 minutes, and reocclusion was totally inhibited.