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
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.