Unique Overlap in the Prerequisites for Thrombin Inhibition and Oral Bioavailability Resulting in Potent Oral Antithrombotics
| Autor: | Jan Kelder, Sjoerd F. van Aelst, Co A.M. Peters, Theo G. van Dinther, Peter D. J. Grootenhuis, A. Visser, Hans Lucas, Anton E.P. Adang, Johannes Bernardus Maria Rewinkel, D.G. Meuleman, Martin J. Smit, Adrianus Petrus Antonius De Man, G.M.T. Vogel, Constant A. A. van Boeckel |
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| Rok vydání: | 2002 |
| Předmět: |
Models
Molecular Administration Oral Biological Availability Biological Transport Active Tripeptide In Vitro Techniques Crystallography X-Ray Structure-Activity Relationship Dogs Thrombin Fibrinolytic Agents Pharmacokinetics Oral administration Drug Discovery medicine Animals Humans Enzyme Inhibitors Aorta Dose-Response Relationship Drug biology Chemistry Thrombosis Rats Bioavailability Biochemistry Enzyme inhibitor biology.protein Molecular Medicine Caco-2 Cells Oligopeptides Fibrinolytic agent Half-Life medicine.drug Discovery and development of direct thrombin inhibitors |
| Zdroj: | Journal of Medicinal Chemistry. 45:4419-4432 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Despite intense research over the last 10 years, aided by the availability of X-ray structures of enzyme-inhibitor complexes, only very few truly orally active thrombin inhibitors have been found. We conducted a comprehensive study starting with peptide transition state analogues (TSA). Both hydrophobic nonpeptide analogues as well as hydrophilic peptidic analogues were synthesized. The bioavailability in rats and dogs could be drastically altered depending on the overall charge distribution in the molecule. Compound 27, a tripeptide TSA inhibitor of thrombin, showed an oral bioavailability of 32% in rats and 71% in dogs, elimination half-lives being 58 and 108 min, respectively. The thrombin inhibition constant of compound 27 was 1.1 nM, and in an in vivo arterial flow model, the ED(50) was 5.4 nmol/kg.min, comparable to known non-TSA inhibitors. A molecular design was found that combines antithrombotic efficiency with oral bioavailability at low dosages. |
| Databáze: | OpenAIRE |
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