title: 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.
authors.affiliation: Department of Cardiovascular Biochemistry, Bristol-Myers Squibb Institute for Pharmaceutical Research, Wallingford, CT 06492-7660.
authors.forename: J S
authors.initials: JS
authors.lastname: Fleming
authors.forename: J O
authors.initials: JO
authors.lastname: Buchanan
authors.forename: S M
authors.initials: SM
authors.lastname: Seiler
authors.forename: N A
authors.initials: NA
authors.lastname: Meanwell
mesh_terms: D000818:Animals; D004285:Dogs; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D011817:Rabbits; D012995:Solubility; D015912:Thrombolytic Therapy; D013927:Thrombosis / Q000188:drug therapy; D014867:Water
chemical_list: D005343:Fibrinolytic Agents; D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D011804:Quinolines; D014867:Water; C069965:BMY 21638; C062501:1,3-dihydro-7,8-dimethyl-2H-imidazo(4,5-b)quinolin-2-one; C069964:BMY 43351