Unique overlap in the prerequisites for thrombin inhibition and oral bioavailability resulting in potent oral antithrombotics.
Journal - Journal of medicinal chemistry (United States )
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.
|ISSN : ||0022-2623|
|Mesh Heading : ||Administration, Oral Animals Aorta Biological Availability Biological Transport, Active Caco-2 Cells Crystallography, X-Ray Dogs Dose-Response Relationship, Drug Enzyme Inhibitors Fibrinolytic Agents Half-Life Humans Models, Molecular Oligopeptides Rats Structure-Activity Relationship Thrombin Thrombosis chemistry pharmacology chemistry pharmacology chemistry pharmacology prevention & control|
|Mesh Heading Relevant : ||chemical synthesis chemical synthesis chemical synthesis antagonists & inhibitors|