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SSR182289A, a selective and potent orally active thrombin inhibitor
Jean-Michel Altenburger1, Gilbert Y Lassalle, Mostapha Matrougui
1Sanofi-Synthélabo Research, Cardiovascular-Thrombosis Department, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, Cedex, France.
Bioorganic & Medicinal Chemistry
|March 19, 2004
Summary
SSR182289A 1 is a novel, orally active thrombin inhibitor. This potent compound effectively reduces thrombosis in rat models and shows promise for further development.
Area of Science:
- Medicinal Chemistry
- Pharmacology
Background:
- Thrombin is a key enzyme in the coagulation cascade.
- Development of orally active inhibitors is crucial for antithrombotic therapy.
Purpose of the Study:
- To describe the discovery and characterization of SSR182289A 1, a novel orally active thrombin inhibitor.
- To evaluate the in vitro and in vivo antithrombotic efficacy of SSR182289A 1.
Main Methods:
- Rational drug design and optimization.
- Convergent synthesis utilizing palladium catalysis (Suzuki and Sonogashira reactions).
- In vitro enzyme inhibition assays and in vivo antithrombotic rat models.
Main Results:
- SSR182289A 1 exhibits a unique chemical structure with a biphenyl sulfonyl motif, a 3-amino-pyridine, and a difluoropiperidine.
- The compound is a potent inhibitor of thrombin activity in vitro.
- SSR182289A 1 demonstrated significant oral antithrombotic activity in three rat models.
Conclusions:
- SSR182289A 1 is a potent, orally bioavailable thrombin inhibitor.
- Structural analysis provides insight into its mechanism of action.
- SSR182289A 1 has been selected for further preclinical development.