R 68 070: Thromboxane A2 Synthetase Inhibition and Thromboxane A2/Prostaglandin Endoperoxide Receptor Blockade Combined in One Molecule - I. Biochemical Profile In Vitro

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Abstract
R 68 070 or (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]- methylen]amino]oxy] pentanoic acid (Janssen Research Foundation, Belgium) combines specific thromboxane A2 (TXA2) synthetase inhibition with TXA2/prostaglandin endoperoxide receptor blockade in one molecule. In vitro, the compound specifically inhibits the production of TXB2 from [14C] arachidonic acid by washed human platelets (IC50 = 8.2 × 10-9 M) and by platelet microsomes (IC50 = 3.6 × 10-9 M), of MDA (IC50 = 1.91 × 10-8 M) and of TXB2 (IC50 = 1.47 × 10-8 M) by thrombin-coagulated human platelet-rich plasma (P.R.P.) and whole blood respectively and increases the levels of PGD2, PGE2, PGF2α and 6-keto-PGF1α. The activity of cyclo-oxygenase-, prostacyclin synthetase-, 5-, 12- and 15-lipoxygenase-enzymes are not affected. Additionally, R 68 070 inhibits human platelet aggregation in P.R.P. induced by U 46619 3 × 10-7 M to 2 × 10-6 M (IC50 = 2.08 × 10-6 M to 2.66 × 10-5 M), collagen 0.5 to 2 μg/ml (IC50 = 2.85 × 10-6 M to 4.81 × 10-5 M), arachidonic acid 7.5 × 10-4 M to 2 × 10- M (IC50 = 2.1 × 10-8 M to 3.3 × 10-8 M) and the U 46619 (1 × 10-7 M)-induced accumulation of [32P] phosphatidic acid (IC50 = 5.24 × 10-7 M) in washed human platelets. Collagen (0.75 μg/ml)-induced ATP release (IC50 = 4.1 × 10-6 M), ADP (1 to 2.5 × 10-6 M)-induced second wave aggregation (IC50 = 3.19 × 10-6 M) in P.R.P. as well as the collagen (1 μg/ml)-induced adhesion/aggregation reaction in human whole blood (IC50 = 1.02 × 10-5 M) are reduced as well by the compoun. Primary platelet reactions induced by serotonin, ADP, PAF, or A 23187, platelet adenylate cyclase- and cAMP phosphodiesterase-activity, and platelet inhibitory activities of PGD2, PGI2, PGE2, PGE1 are not modified by R 68 070. This biochemical profile is compatible with a dual mechanism of action of R 68 070, namely TXA2 synthetase inhibition at low concentrations, plus additionally TXA2/prostaglandin endoperoxide receptor blockade at higher concentrations