ABSTRACT
Design, synthesis and biochemical evaluation of a series of novel non-covalent thrombin inhibitors with a 1-amidinopiperidine moiety are presented. Replacement of the planar benzamidine group in azaphenylalanine derivatives with 1-amidinopiperidine resulted in lower activity but higher selectivity for this type of compounds. The binding conformation of inhibitors in the active site of thrombin was revealed by molecular modelling studies.
Subject(s)
Piperidines/chemical synthesis , Piperidines/pharmacology , Thrombin/antagonists & inhibitors , Blood Coagulation/drug effects , Blood Coagulation Tests , Drug Design , Humans , In Vitro Techniques , Indicators and Reagents , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Conformation , Partial Thromboplastin Time , Prothrombin Time , Spectrophotometry, Infrared , Thrombin Time , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/chemistry , Trypsin Inhibitors/pharmacologyABSTRACT
New inhibitors of serine proteases with azaphenylalanine scaffold were synthesized and their activity was evaluated in vitro. We studied the effect of different substituents in the part of a molecule that binds in the distal pocket of the thrombin active site. Modifications generally led to decreased activity, however two derivatives are promising lead compounds as new thrombin and dual thrombin-factor Xa inhibitors.
Subject(s)
Phenylalanine/analogs & derivatives , Phenylalanine/chemical synthesis , Phenylalanine/pharmacology , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacology , Thiadiazoles/chemical synthesis , Thiadiazoles/pharmacology , Chromatography, Thin Layer , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mass Spectrometry , Spectrophotometry, Infrared , Structure-Activity Relationship , Thrombin/antagonists & inhibitorsABSTRACT
Design, synthesis and biological evaluation of a series of novel non-covalent azaphenylalanine thrombin inhibitors are presented. Replacement of the basic benzamidine moiety in azaphenylalanine derivatives by benzylamine (P1 part of a molecule) and the introduction of a N-cyclopentyl-N-methylamine moiety in the P2 part of a molecule resulted in the thrombin inhibitor LK-733 with greatly increased selectivity against trypsin and an in vitro Ki of 31 nM.
