title: Structure-based design of novel potent nonpeptide thrombin inhibitors.
abstract: The clinical syndromes of thromboembolism are evoked by an excessive stimulation of the coagulation cascade. In this context, the serine protease thrombin plays a key role. Considerable efforts have therefore been devoted to the discovery of safe, orally active inhibitors of this enzyme. On the basis of the X-ray crystal structure of the peptide-like thrombin inhibitor NAPAP complexed with bovine thrombin, we have designed a new structural class of nonpeptidic inhibitors employing a 1,2,5-trisubstituted benzimidazole as the central scaffold. Supported by a series of X-ray structure analyses, we optimized the activity of these compounds. Thrombin inhibition in the lower nanomolar range could be achieved although the binding energy mainly results from nonpolar, hydrophobic interactions. To improve in vivo potency, we increased the overall hydrophilicity of the molecules by introducing carboxylate groups. The very polar compound 24 (BIBR 953) exhibited the most favorable activity profile in vivo. This zwitterionic molecule was converted into the double-prodrug 31 (BIBR 1048), which showed strong oral activity in different animal species. On the basis of these results, 31 was chosen for clinical development.
authors.affiliation: Boehringer Ingelheim Pharma KG, Research Division, Birkendorfer Strasse 65, D-88397 Biberach/RISS, Germany. norbert.hauel@bc.boehringer-ingelheim.de
authors.forename: Norbert H
authors.initials: NH
authors.lastname: Hauel
authors.forename: Herbert
authors.initials: H
authors.lastname: Nar
authors.forename: Henning
authors.initials: H
authors.lastname: Priepke
authors.forename: Uwe
authors.initials: U
authors.lastname: Ries
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Stassen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wienen
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002417:Cattle; D018360:Crystallography, X-Ray; D000069604:Dabigatran; D004353:Drug Evaluation, Preclinical; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008253:Macaca mulatta; D008958:Models, Molecular; D010314:Partial Thromboplastin Time; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: C453961:BIBR 953; D001562:Benzimidazoles; D005343:Fibrinolytic Agents; D011355:Prodrugs; D011725:Pyridines; D015842:Serine Proteinase Inhibitors; D013917:Thrombin; D000069604:Dabigatran