title: Unique overlap in the prerequisites for thrombin inhibition and oral bioavailability resulting in potent oral antithrombotics.
abstract: 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.
authors.affiliation: Research and Development, Lead Discovery Unit Chemistry Group, NV Organon. ton.adang@organon.com
authors.forename: Anton E P
authors.initials: AE
authors.lastname: Adang
authors.forename: Adrianus P A
authors.initials: AP
authors.lastname: de Man
authors.forename: Gerard M T
authors.initials: GM
authors.lastname: Vogel
authors.forename: Peter D J
authors.initials: PD
authors.lastname: Grootenhuis
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Smit
authors.forename: Co A M
authors.initials: CA
authors.lastname: Peters
authors.forename: Arie
authors.initials: A
authors.lastname: Visser
authors.forename: Jos B M
authors.initials: JB
authors.lastname: Rewinkel
authors.forename: Theo
authors.initials: T
authors.lastname: van Dinther
authors.forename: Hans
authors.initials: H
authors.lastname: Lucas
authors.forename: Jan
authors.initials: J
authors.lastname: Kelder
authors.forename: Sjoerd
authors.initials: S
authors.lastname: van Aelst
authors.forename: Dick G
authors.initials: DG
authors.lastname: Meuleman
authors.forename: Constant A A
authors.initials: CA
authors.lastname: van Boeckel
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001011:Aorta; D001682:Biological Availability; D001693:Biological Transport, Active; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000517:prevention & control
chemical_list: D004791:Enzyme Inhibitors; D005343:Fibrinolytic Agents; D009842:Oligopeptides; D013917:Thrombin