ON THE BIOISOSTERIC POTENTIAL OF DIAZINES - DIAZINE ANALOGS OF THE COMBINED THROMBOXANE A(2) RECEPTOR ANTAGONIST AND SYNTHETASE INHIBITOR RIDOGREL

In this SAR study the bioisosteric potential of diazines in the field of combined antithrombotic thromboxane A(2) synthetase inhibitors and receptor antagonists was investigated. In this context, two series of (E)- and -omega-[[(aryldiazinylmethylene)amino]oxy]alkanoic acids were synthesized of which pentanoic acid derivatives with a 2-pyrazinyl, 4 -pyridazinyl, or 6-pyrimidinyl group were found to exhibit this dual a ctivity, while 4-pyrimidinyl as well as 3-pyridazinyl analogues showed only receptor antagonistic activity and 2-pyrimidinyl congeners were inactive. In the series of diazine analogues of Ridogrel (1), replacem ent of the 3-pyridyl group by a 2-pyrazinyl, 4-pyridazinyl, or 5-pyrim idinyl moiety led to compounds that inhibit thromboxane A(2) synthetas e in gel-filtered human platelets comparable to 1 (IC50 Of 0.006, 0.01 6, and 0.039 mu M, respectively, versus 0.007 mu M) Radioligand-bindin g studies with [H-3]SQ 29,548 in washed human platelets revealed that these diazine analogues block the thromboxane Az receptor with an IC50 of 11, 6.0, and 1.5 mu M, respectively. This compares well with the I C50 = 1.7 mu M of 1. Finally, testing of inhibition of collagen-induce d platelet aggregation in human platelet-rich plasma with 2-pyrazinyl, 4-pyridazinyl, or 5-pyrimidinyl congeners of Ridogrel indicated that these heteroaromatic moieties may serve as bioisosteric substitutes of a 3-pyridyl group in dual-acting antiplatelet agents.