Conclusion
The parenteral agent efegatran was chosen for clinical evaluation after extensive SAR studies and subsequent collaborations with the HIDR. It was studied extensively in Phase 1 and Phase 2 clinical trials to determine if it could provide superior benefits to heparin for cardiovascular patients with unstable angina or thrombolysis during acute myocardial infarction. Analysis of data from Phase 2 clinical trials demonstrated that efegatran exhibited equivalent efficacy to heparin. As a consequence further development with this parenteral agent was discontinued.
Compound 26 was discovered from the continuation of the SAR and was evaluated in Phase 1 trials as a potential oral antithrombotic agent. Although plasma anticoagulant activity of compound 26 was prolonged, in a dose- and time-dependent manner after oral administration of an aqueous solution, the half-life of the anticoagulant activity approximated 2 hr and practical utility may be limited. In addition, compound 26 exhibited a considerable reduction in oral exposure when administered immediately after eating. The development of a compound with a longer half-life and minimal food effects would present an opportunity for the development of a novel oral anticoagulant agent. Recent reviews on thrombin inhibitors may provide additional insights for the reader (Scarborough, 1995; Edmunds and Rapundalo, 1996).
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Shuman, R.T., Gesellchen, P.D. (2002). Development of an Orally Active Tripeptide Arginal Thrombin Inhibitor. In: Borchardt, R.T., Freidinger, R.M., Sawyer, T.K., Smith, P.L. (eds) Integration of Pharmaceutical Discovery and Development. Pharmaceutical Biotechnology, vol 11. Springer, Boston, MA. https://doi.org/10.1007/0-306-47384-4_4
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