title: New thrombin inhibitors based on D-cha-Pro-derivatives.
abstract: A series of new analogs with modifications in the C-terminal residue were prepared based on the known thrombin inhibitor D-Phe-Pro-agmatine. These include several compounds alkylated at the N delta-, N omega- and N omega'-atoms of the guanidino group and a number of inhibitors derived from commercially available diamines. All analogs with alkylation of the guanidino group showed very poor activity. In contrast, the most potent and selective inhibitor with a cyclic and basic residue in the P1-position was found to be Ph-CH2-SO2-D-Cha-Pro-4-(amidomethyl) amidinopiperidine 11 with a Ki of 0.27 nM. In addition, a number of compounds were synthesized, in which the basic amidino group of the P1-residue was replaced by a hydroxyl group. Although the inhibition constants of these phenol derivatives showed still remarkable potency (16, Ki = 130 nM), their activity in clotting assays was strongly reduced.
authors.affiliation: Inst. of Biochemistry & Biophysics, Friedrich Schiller University, Jena, Germany. steinmetzer@merlin.biologie.uni-jena.de
authors.forename: T
authors.initials: T
authors.lastname: Steinmetzer
authors.forename: M
authors.initials: M
authors.lastname: Batdorsdhjin
authors.forename: P
authors.initials: P
authors.lastname: Kleinwächter
authors.forename: L
authors.initials: L
authors.lastname: Seyfarth
authors.forename: G
authors.initials: G
authors.lastname: Greiner
authors.forename: S
authors.initials: S
authors.lastname: Reissmann
authors.forename: J
authors.initials: J
authors.lastname: Stürzebecher
mesh_terms: D000376:Agmatine / Q000031:analogs & derivatives; D000925:Anticoagulants / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology*; D010636:Phenols / Q000737:chemistry; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry; D011392:Proline / Q000031:analogs & derivatives; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D000925:Anticoagulants; D009842:Oligopeptides; D010636:Phenols; D015842:Serine Proteinase Inhibitors; C028544:cyclohexylalanine; D010649:Phenylalanine; D000376:Agmatine; D011392:Proline; D013917:Thrombin