AGENTS COMBINING THROMBOXANE RECEPTOR ANTAGONISM WITH THROMBOXANE SYNTHASE INHIBITION - [[[2-(1H-IMIDAZOL-1-YL)ETHYLIDENE]AMINO]OXY] ALKANOIC ACIDS

A new class of compounds combining thromboxane-A(2) (TxA(2)) receptor antagonism and thromboxane synthase inhibition is described. A first s eries of(E)- and (Z)-[[[2-(1H-imidazol- 1-yl)ethylidene]amino] oxy]pen tanoic acids showed relevant thromboxane synthase inhibition associate d with weak TxA(2) receptor antagonism, while a series of azol-1-yl)-3 -phenylpropylidene]amino]oxy]pentanoic acids, structurally derived fro m the former, showed potent and well-balanced dual activity. Structura l requirements for significant single and dual activity are discussed. Two close congeners of the latter series, (+/-)-(E)-5-[[[1-cyclohexyl -2-(1H-imidazol- 1-yl)-3-phenylpropylidene]amino]oxy]pentanoic acid 23 c and its p-fluorophenyl analog 23m, inhibited TxB(2) production in vi tro, in rat whole blood during clotting, with IC50 of 0.06 and 0.37 mu M and antagonized the binding of [H-3]SQ 29548 to washed human platel ets, with IC50 of 0.08 and 0.02 mu M, respectively. These two compound s were selected for further pharmacological evaluation and were shown to antagonize U46619-induced platelet aggregation in human platelet ri ch plasma with IC50 of 0.30 and 0.44 mu M, respectively. They were bot h orally available, and in particular 23m caused a long lasting ex viv o TxA(2) synthase inhibition in the fed rat. The levorotatory enantiom er of 23c, stereospecifically synthesized as a model compound, was fou nd to be more potent than racemic 23c with regard to TxA(2) receptor a ntagonism (IC50 = 0.04 mu M) and equivalent to the latter with regard to TxA(2) synthase inhibition. A molecular modeling study concerning t he levorotatory enantiomer of 23c (S), TxA(2), and representative TxA( 2) antagonists of different classes led to the definition of a putativ e pharmacophoric model for the TxA(2) receptor ligands.