Molecular determinants of the platelet aggregation inhibitory activity of carbamoylpiperidines

New organic nitrate-containing benzyloxy isonipecotanilide derivatives with vasodilatory and anti-platelet activity

“…These SAR trends are in reasonable agreement with the supposed mechanism of action of antiplatelet lipophilic (iso)nipecotamides (Dillingham et al, 1989;Feng et al, 1992;Guo et al, 2000), which involves interaction with anionic phospholipids of the platelet membrane as first step and decrease of intraplatelet Ca 2+ concentration as final effect resulting in reduction of platelet activation. Indeed, it had been shown that, by virtue of their lipophilicity and surface activity, lipophilic nipecotamides can penetrate the platelet membranes and interact with anionic phospholipids (mainly phosphatidylinositol, PI, and phosphatidylserine, PS), thereby increasing their resistance to hydrolysis catalyzed by phospholipase-C to the second messengers inositol 1,4,5-triphosphate (IP3) and s,n-1,2-diacylglycerol (DAG) and reducing the concentrations of IP3 and cytosolic Ca 2+ under the levels required for myosin phosphorylation and platelet activation.…”

“…The significant, albeit poorer, activity shown by compounds 1, 12a and 12b may be most likely Marco et al, 2004), similarly to other lipophilic carbamoyl piperidine derivatives (Dillingham et al, 1989;Feng et al, 1992;Guo et al, 2000), are able to inhibit ADP-induced intraplatelet calcium mobilization. It could be reasonably assumed that the lipophilic benzyloxy isonipecotanilide derivatives investigated herewith may act by decreasing the intracellular Ca ++ concentration also in vascular smooth muscle cells.…”

Biochemical studies on blood coagulation mechanism

“…An enzymatic flipping of inner leaflet phosphatidylserine phospholipids to the outer leaflet upon activation of platelets creates an enzymatic surface capable of sustaining the formation of enzymatic complexes composed of coagulation factors which are attracted to the negatively charged surface (19,20). The activation of platelets also results in the release of many molecules from the interior of the platelet needed for clot formation, including fibrinogen, FV and vWF (21).…”

“…All sub-endothelial tissues express the cellular membrane protein TF which is exposed to circulation when the endothelial layer is disrupted. The exposure of TF to circulation is the initiating event in the coagulation portion of hemostasis, termed secondary hemostasis (19,20,21).…”

“…Thrombin zymogen, prothrombin, is a 72 kDa vitamin K-dependent glycoprotein produced in the liver, which circulates as a single chain molecule in human plasma at a concentration of approximately 1.4 µM (21). Prothrombin contains a single Gla domain, in which ten glutamic acid residues are converted to γ-carboxyglutamic acids (Gla) by the vitamin K-dependent enzyme γ-glutamyl carboxylase, two Kringle domains, and a protease domain (Figure 1.10) (140).…”