title: Synthesis and structure-activity relationships of potent thrombin inhibitors: piperazides of 3-amidinophenylalanine.
abstract: Thrombin is the key enzyme in the blood coagulation system, and inhibitors of its proteolytic activity are of therapeutic interest since they are potential anticoagulants. The most potent inhibitor of the benzamidine type is N alpha-[(2-naphthylsulfonyl)glycyl]-4-amidinophenylalanylpiperid ide (NAPAP). However, NAPAP and other benzamidine derivatives do not show favorable pharmacological properties; above all, they have very low systemic bioavailability after oral administration. The goal of designing new compounds was to obtain potent inhibitors with improved pharmacokinetic properties. Piperazide derivatives of 3-amidinophenylalanine as the key building block were synthesized. The piperazine moiety opened the possibility to introduce quite different substituents on the second nitrogen using common synthetic procedures. Some of the newly synthesized compounds are potent inhibitors of thrombin and offer an approach to study structure-function relationships for inhibition of thrombin and related enzymes and for the improvement of their pharmacokinetic properties.
authors.affiliation: Klinikum der Friedrich-Schiller-Universität Jena, Erfurt, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Stürzebecher
authors.forename: D
authors.initials: D
authors.lastname: Prasa
authors.forename: J
authors.initials: J
authors.lastname: Hauptmann
authors.forename: H
authors.initials: H
authors.lastname: Vieweg
authors.forename: P
authors.initials: P
authors.lastname: Wikström
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001777:Blood Coagulation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D005341:Fibrinolysin / Q000037:antagonists & inhibitors; D006801:Humans; D007202:Indicators and Reagents; D008657:Metabolic Clearance Rate; D010649:Phenylalanine; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011517:Prothrombin Time; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014357:Trypsin / Q000378:metabolism
chemical_list: D000991:Antithrombins; D004151:Dipeptides; D065427:Factor Xa Inhibitors; D007202:Indicators and Reagents; D010879:Piperazines; D010880:Piperidines; D011480:Protease Inhibitors; D010649:Phenylalanine; C038708:N(alpha)-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide; D014357:Trypsin; D013917:Thrombin; D005341:Fibrinolysin