SSR182289A, a selective and potent orally active thrombin inhibitor
| Autor: | Mostapha Matrougui, Paul J. Schaeffer, Zsolt Bocskei, Janine Lorrain, Jean-Marc Herbert, Christopher N. Berry, Jean-Claude Jetha, Stephen E. O'Connor, Lassalle Gilbert, Jean-Michel Altenburger, Jean-Pascal Herault, Catherine Lunven, Daniel Galtier |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Models Molecular Benzylamines Platelet Aggregation Molecular model Stereochemistry Clinical Biochemistry Administration Oral Aminopyridines Pharmaceutical Science Sonogashira coupling Crystallography X-Ray Biochemistry Chemical synthesis Argatroban Structure-Activity Relationship Thrombin Suzuki reaction Drug Discovery medicine Animals Humans Blood Coagulation Molecular Biology Sulfonamides Molecular Structure biology Chemistry Organic Chemistry Hydrogen Bonding Thrombosis Biological activity Rats Disease Models Animal Enzyme inhibitor biology.protein Azetidines Molecular Medicine medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 12:1713-1730 |
| ISSN: | 0968-0896 |
| Popis: | SSR182289A 1 is the result of a rational optimisation process leading to an orally active thrombin inhibitor. The struc- ture incorporates an original 2-(acetylamino)-(1,1 0 -biphenyl)-3-sulfonyl N-terminal motif, a central l-Arg surrogate carrying a weakly basic 3-amino-pyridine, and an unusual 4-difluoropiperidine at the C-terminus. Its synthesis is convergent and palladium catalysis has been employed for the construction of the key C-C bonds: Suzuki coupling for the bis-aryl fragment and Sonogashira reaction for the d-e bond of the central amino-acid chain. The compound is a potent inhibitor of thrombin's activities in vitro and demonstrates potent oral anti-thrombotic potencies in three rat models of thrombosis. The observed in vitro potency could be rationalized through the examination of the interactions within the SSR182289A 1 - thrombin crystal structure. SSR182289A 1, has been therefore selected for further development. # 2004 Elsevier Ltd. All rights reserved. |
| Databáze: | OpenAIRE |
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