Characterization of Bay U 3405, a novel thromboxane A2/endoperoxide receptor antagonist.
The thromboxane A2-receptor antagonistic properties of Bay U 3405 [(3R)-3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbaz o-lepropanoic acid] have been evaluated in various pharmacologic models. Bay U 3405 specifically inhibits platelet aggregation induced by U 46619, collagen, platelet-activating factor, and the second wave of ADP (IC50 0.5, 0.07, 0.3, 0.19 microM) in human plasma. The plasma phase of ADP-induced aggregation is not affected. U 46619-induced platelet aggregation is competitively antagonized (pA2 = 6.3). In humans, ex vivo platelet aggregation is inhibited after oral application of 2 or 50 mg Bay U 3405. Bay U 3405 also specifically and competitively antagonizes U 46619-induced contractions of rabbit aortic rings (pA2 = 7.4). In vivo, Bay U 3405 protects rabbits dose dependently from arachidonic acid or collagen-induced thromboembolism (ED50 1-3 mg/kg p.o). Chronic administration of Bay U 3405 to stroke-prone spontaneously hypertensive rats reduces stroke-related mortality and diminishes the occurrence of cerebral hemorrhages. From these results, we conclude that Bay U 3405 is an orally active, selective, and competitive thromboxane A2-receptor antagonist that may be beneficial in the treatment of cardiovascular or cerebrovascular diseases.
Perzborn
E
E
Institute of Pharmacology, Bayer AG, Wuppertal, FRG.
Fiedler
V B
VB
Seuter
F
F
Stasch
J P
JP
Weber
H
H
Sander
E
E
Böshagen
H
H
Rosentreter
U
U
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000502:physiology; D016718:Arachidonic Acid; D001095:Arachidonic Acids; D001667:Binding, Competitive; D002227:Carbazoles / Q000494:pharmacology* / Q000627:therapeutic use; D002561:Cerebrovascular Disorders / Q000188:drug therapy; D003094:Collagen; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013923:Thromboembolism / Q000139:chemically induced / Q000517:prevention & control; D013931:Thromboxanes / Q000037:antagonists & inhibitors*; D014661:Vasoconstriction / Q000187:drug effects
D001095:Arachidonic Acids; D002227:Carbazoles; D010975:Platelet Aggregation Inhibitors; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013931:Thromboxanes; D016718:Arachidonic Acid; D000244:Adenosine Diphosphate; D003094:Collagen; C063119:ramatroban