title: Preparation and evaluation of PEG-bound thrombin inhibitors based on 4-amidinophenylalanine.
abstract: The dipeptide Mtr-Asp-D-Adf-Pip 10 represents a potent thrombin inhibitor. In comparison to NAPAP, 10 exhibited improved tolerability and a longer half-life in vivo, i.e., 20 +/- 5 min. We have coupled aminopolyethyleneglycolmonomethylether of various molecular weights to the carboxyl moiety of 10 and evaluated their biological properties. First, Mtr-Asp-OBut was coupled to the amino group of the PEG employing TOTU as an activating agent. This was followed by the removal of the OBut protecting group and coupling of D-Adf-Pip using TOTU as well. The PEG-bound thrombin inhibitors showed inhibition constants vs. thrombin in the subnanomolar range, i.e., they were more active than the parent molecule 10. Moreover, the pegylated inhibitors exhibited a longer lasting effect in vivo. In rats the half-life of Mtr-Asn (PEG10000-OMe)-D-Adf-Pip 14 was determined to be 63 min. Mtr-Asn(PEG10000-OMe)-D-Adf-Pip 14 showed a half-life of 120 min in pigs. It could be concluded that these PEG-bound thrombin inhibitors may be employed as versatile drugs for parenteral administration in treating thrombotic disorders.
authors.affiliation: Behringwerke AG, R & D Therapeutics, Marburg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Stüber
authors.forename: R
authors.initials: R
authors.lastname: Koschinsky
authors.forename: M
authors.initials: M
authors.lastname: Reers
authors.forename: D
authors.initials: D
authors.lastname: Hoffmann
authors.forename: J
authors.initials: J
authors.lastname: Czech
authors.forename: G
authors.initials: G
authors.lastname: Dickneite
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D001777:Blood Coagulation / Q000187:drug effects; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010649:Phenylalanine / Q000031:analogs & derivatives*; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000991:Antithrombins; D004151:Dipeptides; D011092:Polyethylene Glycols; D010649:Phenylalanine