ANTITHROMBOTIC OLIGOAMINES

Abstract

We have found that oligoamines of the general formula R2−3X(R=-(CH2)m-NH-(CH2)n-Y) in which X and Y may be aliphatic, alicyc-lic, aromatic or even heterocyclic moieties are a new class of compounds which exhibit platelet aggregation inhibiting and anticoagulant activities in vitro and have antithrombotic properties in vivo. The compound RE 1492 (N,N’,N1’-Tris-4-phenylbutylbenzene-1,3,5-trimethanamine) is chosen as example to demonstrate these effects. In PRP the following IC50 of RE 1492 (inductor in brackets) were measured: 3 ¼mol/L (Collagen), 1 ¼mol/L (ADP, 2ndphase), 7.5 μmol/L (ADP, lstphase), 2,5 μmol/L (A 23187, 2ndphase), 7,5 μmol/L (Ionophor A 23187, lstphase), 30 ¼mol/L (Thrombin). The inhibition of the aggregation Induced by ADP could as well be demonstrated in whole blood. The formation of fibrin was inhibited as shown by the prolongation of the thromboplastin time (Quick) and the partial thromboplastin time (PTT) the first being more sensitive (25% of normal at 50 ymol/L) than the latter (25% of normal at 100 ymol/L). The reason was the inhibition of coagulation factors in the following order: VII (25% of normal at 12.5 ¼mol/L) >WErwnr/IX (25 ¼mol/L) »X (200 μmol/L). The thrombin time remains normal. The antithrombotic properties of RE 1492 were investigated in an in vivo thrombosis model. The formation of platelet thrombi in mesenteric arterioles and venoles of rats (diameterM5 ym) was induced by a laser beam. In controls 1,76±1,14 (SD) shots (50 msec, 50 mW) on the arterioles were necessary for thrombus formation. Twenty minutes after i.v. application of RE 1492 this number rose to 3,18±2,08 (3 mg/kg, p ≤ 0,01, X2-test) and 4,59±1,93 (10 mg/kg, p ≤ 0,01) in arterioles. In venoles of the control animals 1,29±0,45 shots were necessary for thrombus formation. This number rose to 2,11±1,62 (p ≤ 0,05) after 3 mg/kg and 3,28±2,03 (p0,01) after 10 mg/kg. As the number of shots applied was limited to five an average shot number of 5± SD would indicate that no thrombus formation takes place at all. As RE 1492 does neither influence the metabolic pattern of arachidonic acid in platelets nor the activity of phosphodiesterase or adenylatcyclase it is supposed that the oligoamines exert their effects by interaction with phospholipids (PL) resulting in a “membrane stabilization” in platelets and inhibition of PL dependent coagulation factors during fibrin formation.