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Antithrombotic action of the orally available thromboxane A 2 receptor antagonist S‐1452 (d‐s‐145 Ca) in rodents
Author(s) -
Jyoyama Hirokuni,
Hori Yozo,
Hatakeyama Hisao,
Asanuma Fujio,
Kurosawa Atsushi
Publication year - 1993
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430300204
Subject(s) - chemistry , antithrombotic , antagonist , thromboxane , pharmacology , aspirin , receptor antagonist , thromboxane a2 , fibrinolytic agent , calcium , oral administration , platelet , receptor , medicine , biochemistry , organic chemistry
The thromboxane A 2 (TXA 2 ) receptor antagonist, S‐1452, calcium salt of a steroselectively synthesized d‐enantiomer of the racemate S‐145, calcium 5(Z)‐1R,2S,3S,4S‐7‐[3‐phenylsulfonylaminobicyclo[2.2.1]hept‐2‐yl]‐5‐heptenoate dihydrate, was examined for its antithrombotic action in vivo, in mice and rats. Orally administered S‐1452 dose‐dependently prolonged the bleeding time which was measured by a tail transection method. The effect was observed at doses above 1 mg/kg in both animals. S‐1452 clearly prevented U46619‐induced sudden death in mice and its ED 50 value for the prevention was 0.47 mg/kg at 1 h after oral administration. It was more potent and long‐acting than reference compounds such as ONO‐3708 and SQ‐26548. The preventive effect of S‐1452 was also observed in arachidonate‐induced sudden death, although much larger doses were required in comparison with the case of the U‐46619‐induced response (ED 50 : 4.6 mg/kg p.o., at 30 min; 3.1 mg/kg p.o., at 60 min after S‐1452). Aspirin, used as a reference compound, was much less active than S‐1452 (ED 50 : 85.9 mg/kg p.o., at 30 min; 88.2 mg/kg p.o., at 60 min after aspirin). The pharmacologically active moiety of S‐1452, d‐S‐145, was several times more potent than the opposite enantiomer 1‐S‐145 in the prolongation of the bleeding time in rats, and in the prevention of the U46619‐induced sudden death in mice. These stereoselective efficacies suggest that S‐1452 causes its antithrombotic action by blocking TXA 2 receptors in vivo. S‐1452 significantly reduced collagen‐induced thrombocytopenia in mice at doses above 0.1 mg/kg p.o. In rats, the compound improved clearly collagen‐induced abnormal electrocardiogram. The minimum effective doses were 1 mg/kg for S‐1452, 15 mg/kg for ONO‐3708, and 10 mg/kg for OKY‐046, 60 min after oral administration. It is concluded that S‐1452 is a very potent and orally available antithrombotic compound. © 1993 wiley‐Liss, Inc.