Samixogrel

Thromboxane A(2) (TxA(2)), a bioactive metabolite of the Arachidonic acid (AA), is a potent mediator of platelet aggregation, vasoconstriction and bronchoconstriction. It plays an important role in major human diseases, such as myocardial infraction, unstable angina, pregnancy-induced hypertension and preeclampsia, thrombosis and thrombotic disorders, pulmonary hypertension, asthma, septic shock, atherosclerosis, lupus nephritis, and Raynaud's phenomenon. Thus, TxA(2) is a therapeutic target for many research groups. A number of TXA(2) receptor antagonists as well as thromboxane synthase inhibitors have been developed. In this research we review and evaluate new quantitative structure activity relationships of thromboxane synthase inhibitors and thromboxane receptor antagonists, using the C-QSAR program of Biobyte. Lipophicity, as Clog P is a significant physicochemical parameter for this biological response. CMR/MR molar refractivity as well as sterimol parameters seemed to be important as well Molecular Volume. Electronic effects with the exception of σ Hammett's constant are not found to govern the biological activity. The derived equations will be very helpful for the design of new potent molecules.

Drugs that inhibit TxA2 synthesis are used to reduce platelet aggregation. The aim of this study was to compare the effects of a cyclo‐oxygenase (COX) inhibitor (acetylsalicylic acid, ASA), a thromboxane synthetase (TxS) inhibitor (dazoxiben) and a dual TxS inhibitor and TxA2 receptor blocker (DT‐TX 30) on platelet aggregation and the platelet‐subendothelium interaction in flow conditions.The techniques used in this in vitro study were platelet aggregometry in whole blood, and measurement of platelet thromboxane B2 and prostaglandin E2 production and leucocyte production of 6‐keto‐PGF1α. The platelet‐subendothelium interaction was evaluated in rabbit aorta subendothelium preparations exposed to flowing blood at a shear stress of 800 s−1. Morphometric methods were used to calculate the percentage of subendothelium occupied by platelets.The 50% inhibitory concentration (IC50) of DT‐TX 30 in whole blood was in the range of 10−7 μM (induced with collagen or arachidonic acid) to 10−5 μM (induced with thrombin) or 10−4 (induced with ADP). IC50 values under all experimental conditions were lower with DT–TX 30 than with ASA. For thromboxane B2 the IC50 were: ASA 0.84±0.05 μM, dazoxiben 765±54 μM, DT–TX 30 8.54±0.60 μM. Prostaglandin E2 was inhibited only by ASA (IC50 1.21±0.08 μM). Leucocyte 6‐keto‐PGF1α was inhibited by ASA (IC50 6.58±0.76 μM) and increased by dazoxiben and DT–TX 30. The greatest reduction in percentage subendothelial surface occupied by platelets after blood perfusion was seen after treatment with DT–TX 30 in the range of concentrations that inhibited collagen‐induced platelet aggregation (control group: 31.20±3.8%, DT‐TX 30 at 0.1 μM: 10.71±0.55%, at 1.0 μM: 6.53±0.44%, at 5.0 μM; 1.48±0.07%). All three drugs reduced thrombus formation, although ASA (unlike dazoxiben or DT–TX 30) increased the percentage surface occupied by adhesions.In conclusion, the effect of specific blockage of TxS together with blockage of membrane receptors for TxA2 can surpass the effect of ASA in inhibiting the platelet‐subendothelium interaction in flow conditions.British Journal of Pharmacology (2002) 137, 1082–1088. doi:10.1038/sj.bjp.0704963