Aromatic amidines: inhibitory effect on purified plasma serine proteinases, blood coagulation and platelet aggregation.
The inhibitory effect of benzamidine as well as of 1,3-di-(p-amidinophenoxy)-2,2-bis-(p-amidinophenoxymethyl)propane (TAPP-H) and TAPP-halo derivatives (with Cl, Br or I) on (i) the catalytic properties of purified plasma serine proteinases (notably, factor Xa, factor VIIa, thrombin and plasmin), (ii) blood coagulation, and (iii) platelet aggregation was investigated in vitro. For all the enzyme/inhibitor systems examined, the inhibition patterns were strictly competitive, and titrations conformed to simple equilibria. The inhibitory effect of TAPP-H and TAPP-halo derivatives is higher, by at least 10-fold, than that of benzamidine, which binds at the primary specificity subsite (S1) of serine proteinases and is commonly taken as a molecular inhibitor model. The high inhibitory effect of aromatic tetraamidines has been interpreted taking into account an additional productive binding for a second benzamidine or halo-benzamidine moiety to the enzyme surface. As a whole, the data reported here indicate that aromatic amidines inhibit the plasma serine proteinases involved in different steps of haemostasis (coagulation and platelet aggregation) as well as clot lysis under physiological-like conditions in vitro.
Ferroni
R
R
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Italy.
Menegatti
E
E
Guarneri
M
M
Taddeo
U
U
Ascenzi
P
P
Amiconi
G
G
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D001550:Benzamidines / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects*; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D010974:Platelet Aggregation / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors
D000578:Amidines; D001550:Benzamidines; D015842:Serine Proteinase Inhibitors; C034807:tetra-4-amidinophenoxypropane; C032157:benzamidine