Synthesis and Structure−Activity Relationships of Potent Thrombin Inhibitors:  Piperazides of 3-Amidinophenylalanine

• Published in: Journal of medicinal chemistry 1997-09, Vol.40 (19), p.3091-3099
• Main Authors: Stürzebecher, Jörg, Prasa, Dagmar, Hauptmann, Jörg, Vieweg, Helmut, Wikström, Peter
• Format: Article
• Language: English
• Subjects: Animals; Antithrombins - chemical synthesis; Antithrombins - chemistry; Antithrombins - pharmacology; Binding Sites; Biological and medical sciences; Blood Coagulation - drug effects; Blood. Blood coagulation. Reticuloendothelial system; Crystallography, X-Ray; Dipeptides - chemical synthesis; Dipeptides - chemistry; Dipeptides - pharmacokinetics; Dipeptides - pharmacology; Factor Xa Inhibitors; Fibrinolysin - antagonists & inhibitors; Humans; Indicators and Reagents; Medical sciences; Metabolic Clearance Rate; Pharmacology. Drug treatments; Phenylalanine; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Piperidines - chemistry; Piperidines - pharmacokinetics; Piperidines - pharmacology; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Prothrombin Time; Rats; Stereoisomerism; Structure-Activity Relationship; Thrombin - antagonists & inhibitors; Thrombin - chemistry; Trypsin - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960668h

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 α-[(2-naphthylsulfonyl)glycyl]-4-amidinophenylalanylpiperidide (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.