Download PDF
Thromb Haemost 1978; 39(01): 167-176
DOI: 10.1055/s-0038-1646666
Original Article
Schattauer GmbH Stuttgart

Effect of 1-Methyl-2-Mercapto-5-(3-Pyridyl)-Imidazole (KC-6141) on Rabbit Platelet Aggregation in Vitro and Rat Platelet Retention

Teruhiko Umetsu
The Central Research Laboratory, Kaken Chemical Co., Ltd., Honkomagome 2–28–8, Bunkyo-Ku, Tokyo 113, Japan
,
Tadakatsu Kato
The Central Research Laboratory, Kaken Chemical Co., Ltd., Honkomagome 2–28–8, Bunkyo-Ku, Tokyo 113, Japan
› Author Affiliations
Further Information

Publication History

Received 24 February 1977

Accepted 24 July 1977

Publication Date:
12 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

Effect of l-methyl-2-mercapto-5-(3-pyridyl)-imidazole (KC-6141) on rabbit platelet aggregation in vitro and rat platelet retention were investigated.

In the in vitro study, KC-6141 inhibited ADP-induced aggregation by 27% at 5× 10−4M, being more active than dipyridamole but much less than adenosine. Inhibition of arachidonic acid-and collagen-induced aggregation by KC-6141 was more effective than that of ADP-induced one and its ED50 was 2.1×10−5 and 8×10−5M, respectively. KC-6141 was 10 and 4 times more potent than aspirin in arachidonic acid-and collagen-induced aggregation, respectively. The dose-response curve of KC-6141 was parallel to that of aspirin, suggesting it is an aspirin-like compound.

In the platelet retention study, a method for determining platelet retention in rats was devised so that platelet retention can be measured with a volume of blood as small as possible. By use of the method, effects of KC-6141, aspirin and dipyridamole were compared. When administered intraperitoneally at 100 mg/kg, KC-6141 indicated 54.8% inhibition of platelet retention, whereas aspirin and dipyridamole showed only 23.5 and 5.2% inhibition, respectively. On the oral administration at 200 mg/kg, KC-6141 inhibited by 60.8% and its ED50 was 125 mg/kg. The activity lasted over 32 hr.

The above results demonstrated that KC-6141 is a compound with more potent action on the platelet aggregation, as well as on the platelet retention than aspirin and dipyridamole – a known antithrombotic drug.

 

  • References

  • 1 Born GVR. 1962; Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 194: 972
    PubMedGoogle Scholar
  • 2 Born GVR, Cross MJ. 1963; The aggregation of blood platelets. Nature 168: 178
    PubMedGoogle Scholar
  • 3 Born GVR, Honour AJ, Mitchell JRA. 1964; Inhibition by adenosine and by 2-chloroadenosine of the formation and embolization of platelet thrombi. Nature 202: 761
    CrossrefPubMedGoogle Scholar
  • 4 Bowie EJW, Owen CA, Thompson JH, Didisheim P. 1969; Platelet adhesiveness in von Willebrand’s disease. American Journal of Clinical Pathology 52: 69
    CrossrefPubMedGoogle Scholar
  • 5 Brecher G, Cronkite EP. 1950; Morphology and enumeration of human blood platelets. Journal of Applied Physiology 3: 365
    CrossrefPubMedGoogle Scholar
  • 6 Cucuianu MP, Nishizawa EE, Mustard JF. 1971; Effect of pyrimido-pyrimidine compounds on platelet function. Journal of Laboratory and Clinical Medicine 77: 958
    PubMedGoogle Scholar
  • 7 Didisheim P. 1972. Animal models useful in the study of thrombosis and antithrombotic agents. In: Spaet TH. (ed.) Progress in Hemostasis and Thrombosis. Grune and Stratton, Inc.; 165
    Google Scholar
  • 8 Emmons PR, Hampton JR, Harrison MJG, Honour AJ, Mitchell JRA. 1967; Effect of prostaglandin E1 on platelet behaviour in vitro and in vivo. British Medical Journal 2: 468
    CrossrefPubMedGoogle Scholar
  • 9 Evans G, Packham MA, Nishizawa EE, Mustard JF, Murphy EA. 1968; The effect of acetylsalicylie acid on platelet function. Journal of Experimental Medicine 128: 877
    CrossrefPubMedGoogle Scholar
  • 10 Forbes CD, McNicol GP, Douglas AS. 1969; Action of a pyrimido-pyrimidine compound on platelet behaviours in vitro. British Medical Journal 2: 483
    CrossrefPubMedGoogle Scholar
  • 11 Hamberg M, Svensson J, Wakabayashi T, Samuelsson B. 1974; a Isolation and structure of two prostaglandin endoperoxides that cause platelet aggregation. Proceedings of the National Academy of Sciences of the United States of America 71: 345
    CrossrefPubMedGoogle Scholar
  • 12 Hamberg M, Svensson J, Samuelsson B. 1974; b Prostaglandin endoperoxides. A new concept concerning the mode of action and release of prostaglandin. Proceedings of the National Academy of Sciences of the United States of America 71: 3824
    CrossrefPubMedGoogle Scholar
  • 13 Hamberg M, Svensson J, Samuelsson B. 1975; Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides. Proceedings of the National Academy of Sciences of the United States of America 72: 2994
    CrossrefPubMedGoogle Scholar
  • 14 Hassanein AA, Turpie AGG, McNicol GP, Forbes CD, Douglas AS. 1970; The action of pyrimido-pyrimidine compounds on platelet behaviour in vitro. Thrombosis et Diathesis Haemorrhagica Suppl 42: 277
    PubMedGoogle Scholar
  • 15 Hirsh J, Gent M, Genton E. 1975; The current status of platelet suppressive drugs in the treatment of thrombosis. Thrombosis et Diathesis Haemorrhagica 33: 406
    PubMedGoogle Scholar
  • 16 Horch U, Kadatz R, Kopitar Z, Ritschard J, Weisenberger H. 1970; Pharmacology of dipyridamole and its derivatives. Thrombosis et Diathesis Haemorrhagica Suppl 42: 253
    PubMedGoogle Scholar
  • 17 McNicol GP, Mitchell JRA, Reuter H, Loo JVD. 1974; Platelets in thrombosis. Their clinical significance and the evaluation of potential drugs Thrombosis et Diathesis Haemorrhagica. 31: 379
    PubMedGoogle Scholar
  • 18 Meyer D. 1972. In vitro platelet adhesiveness Methods of study and clinical significance. In: Mannucci PM, Gorini S. (ed.) Platelet Function and Thrombosis. Plenum Press; 123
    Google Scholar
  • 19 Mills DCB, Smith JB. 1971; The influence on platelet aggregation of drugs that affect the accumulation of adenosine 3',5'-cyclic monophosphate in platelets. Biochemical Journal 121: 185
    CrossrefPubMedGoogle Scholar
  • 20 Mustard JF, Kinlough-Rathbone RL, Jenkins CSP, Packham MA. 1972; Modification of platelet function. Annals of the New York Academy of Sciences 201: 343
    CrossrefPubMedGoogle Scholar
  • 21 Mustard JF, Packham MA. 1970; Factors influencing platelet function: Adhesion, release, and aggregation. Pharmacological Reviews 22: 97
    PubMedGoogle Scholar
  • 22 Mustard JF, Packham MA. 1973; Drugs inhibiting platelet function. Biochemical Pharmacology 22: 3151
    CrossrefPubMedGoogle Scholar
  • 23 Mustard JF, Packham MA. 1975; The role of blood and platelets in atherosclerosis and the complication of atherosclerosis. Thrombosis et Diathesis Haemorrhagica 33: 444
    PubMedGoogle Scholar
  • 24 Needleman P, Raz A, Ferrendelli JA, Minkes M. 1977; Application of imidazole as a selective inhibitor of thromboxane synthetase in human platelets. Proceedings of the National Academy of Sciences of the United States of America 74: 1716
    CrossrefPubMedGoogle Scholar
  • 25 Nishizawa EE, Miller WL, Gorman RR, Bundy GL. 1975; Prostaglandin D2as a potential antithrombotic agent. Prostaglandins 9: 109
    CrossrefPubMedGoogle Scholar
  • 26 O'Brien JR. 1968; Effect of anti-inflammatory agents on platelets. Lancet I: 894
    PubMedGoogle Scholar
  • 27 Otsuka K, Amemiya K, Saga K, Kano S, Kumada T. 1974; Antiinflammatory 2-mercapto-(3-pyridyl)-imidazoles. Chemical Abstract 80: 120945 k
    PubMedGoogle Scholar
  • 28 Packham MA, Mustard JF. 1969; The effect of pyrazole compounds on thrombin-induced platelet aggregation. Proceedings of the Society for Experimental Biology and Medicine 130: 72
    PubMedGoogle Scholar
  • 29 Packham MA, Warrior SE, Glynn MF, Sengi AS, Mustard JF. 1967; Alteration of the response of platelets to surface stimuli by pyrazole compounds. Journal of Experimental Medicine 126: 171
    CrossrefPubMedGoogle Scholar
  • 30 Salzman EW. 1963; Measurement of platelet adhesiveness. A simple in vitro technique demonstrating an abnormality in von Willebrand’s disease. Journal of Laboratory and Clinical Medicine 62: 724
    PubMedGoogle Scholar
  • 31 Salzman EW. 1972; Cyclic AMP and platelet function. New England Journal of Medicine 286: 358
    CrossrefPubMedGoogle Scholar
  • 32 Umetsu T, Sanai K, Kato T. 1976; Effects of bupranolol, a new β-blocker, on platelet functions of rabbit and human in vitro. Thrombosis and Haemostasis 36: 376
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Weiss HJ, Aledort LM, Kochwa S. 1968; The effect of salicylates on the hemostatic properties of platelets in man. Journal of Clinical Investigation 47: 2169
    CrossrefPubMedGoogle Scholar
  • 34 Zucker MB, Peterson J. 1970; Effect of acetylsalicylie acid, other nonsteroidal anti-inflammatory agents, and dipyridamole on human blood platelets. Journal of Laboratory and Clinical Medicine 76: 66
    PubMedGoogle Scholar