6,6-DISUBSTITUTED HEX-5-ENOIC ACID-DERIVATIVES AS COMBINED THROMBOXANE A(2) RECEPTOR ANTAGONISTS AND SYNTHETASE INHIBITORS

A series of omega-disubstituted alkenoic acid derivatives were designe d and synthesized as antithrombotic inhibitors of thromboxane A(2) syn thetase and thromboxane A(2) receptor antagonists. Hexenoic acid deriv atives with a 3-pyridyl group and a 4-(2-benzenesulfonamidoethyl)pheny l substituent were found to be optimal with regard to the dual mode of action. The most potent compound, fonyl)amino)ethyl)phenyl)-6-(3-pyri dyl)hex-5-enoic acid (36), inhibits thromboxane A(2) synthetase in gel -filtered human platelets with an IC50 value of 4.5 +/- 0.5 nM (n = 4) ,whereas an inhibitory effect on cyclooxygenase is seen only at a much higher concentration (IC50: 240 mu M). Radioligand-binding studies wi th [H-3]SQ 29,548 in washed human platelets revealed that 36 blocks th e prostaglandin H-2/thromboxane A(2) receptor with an IC50 Of 19 +/- 5 nM (n = 5) and is therefore 85-fold more potent than another combined thromboxane A(2) synthetase inhibitor/ receptor antagonist, Ridogrel (4). Compound 36 inhibits the collagen-induced platelet aggregation in human platelet-rich plasma and whole blood with an EC(50) of 1 mu M ( Ridogrel: 16 mu M) and 100 nM, respectively, and was selected for furt her development.