SYNTHESIS AND CHARACTERIZATION OF NOVEL THROMBIN INHIBITORS BASED ON 4-AMIDINOPHENYLALANINE

Citation
M. Reers et al., SYNTHESIS AND CHARACTERIZATION OF NOVEL THROMBIN INHIBITORS BASED ON 4-AMIDINOPHENYLALANINE, Journal of enzyme inhibition, 9(1), 1995, pp. 61-72
Citations number
19
Categorie Soggetti
Biology
ISSN journal
87555093
Volume
9
Issue
1
Year of publication
1995
Pages
61 - 72
Database
ISI
SICI code
8755-5093(1995)9:1<61:SACONT>2.0.ZU;2-L
Abstract
Thrombin inhibitors have been thought to play a pivotal role in myocar dial infarct and stroke incidences and their aftermath. Quite some tim e ago potent synthetic thrombin inhibitors became known based on pepti de derivatives D-Phe-Pro-Arg and benzamidine. One of them, fairly well characterised was beta-naphthylsulphonylglycyl-D,L-4-amidino- phenyla lanylpiperidide (NAPAP). NAPAP was prone to being administered intrave nously due to its short plasma half life. Drawbacks to this compound s uch as effects on histamine release and blood pressure may have obstru cted its clinical use. Long half life and oral bioavailability would b e desirable for prophylactic treatment of thrombotic disorders. We hav e used NAPAP as a template for new synthetic compounds to improve some characteristics of its profile. For screening purposes we have invest igated fairly simple surrogate parameters, aspects that were considere d to contribute to pharmacological effects. Potency was correlated to thrombin inhibition, side effects were addressed by specificity toward thrombin as well as reduction in basicity, and plasma half life was c onsidered to be modulated by plasma stability of the compound. Oral bi oavailability would be affected by instability during the passage thro ugh the gut wall. Chemical introduction of a carboxylic group and exch ange of the naphthyl group for 4-methoxy-2,3,6-trimethylphenyl led to a compound that when compared to NAPAP, exhibited a 4-fold increase in thrombin inhibitory activity and a 3-fold increase in trypsin specifi city. Plasma stability decreased to 22 h, however, sufficient enough n ot to play a major role in plasma half life. Gut homogenate stability of the compound has not changed. The potency increase did not translat e into a reduction in IC50-values for the coagulation assay aPTT and T T, in contrast to the IC50-values for thrombin-induced platelet aggreg ation.