R 68 070: thromboxane A2 synthetase inhibition and thromboxane A2/prostaglandin endoperoxide receptor blockade combined in one molecule--I. Biochemical profile in vitro.

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 X 10(-9) M) and by platelet microsomes (IC50 = 3.6 X 10(-9) M), of MDA (IC50 = 1.91 X 10(-8) M) and of TXB2 (IC50 = 1.47 X 10(-8) M) by thrombin-coagulated human platelet-rich plasma (P.R.P.) and whole blood respectively and increases the levels of PGD2, PGE2, PGF2 alpha and 6-keto-PGF1 alpha. 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 X 10(-7) M to 2 X 10(-6) M (IC50 = 2.08 X 10(-6) M to 2.66 X 10(-5) M, collagen 0.5 to 2 micrograms/ml (IC50 = 2.85 X 10(-6) M to 4.81 X 10(-5) M), arachidonic acid 7.5 X 10(-4) M to 2 X 10(-3) M (IC50 = 2.1 X 10(-8) M to 3.3 X 10(-8) M) and the U 46619 (1 X 10(-7) M)-induced accumulation of [32P] phosphatidic acid (IC50 = 5.24 X 10(-7) M) in washed human platelets.(ABSTRACT TRUNCATED AT 250 WORDS)