Agents combining thromboxane receptor antagonism with thromboxane synthase inhibition: [[[2-(1H-imidazol-1-yl)ethylidene]amino]oxy]alkanoic acids

Article abstract of DOI:10.1021/jm00047a016

A new class of compounds combining thromboxane-A₂ (TxA₂) receptor antagonism and thromboxane synthase inhibition is described. A first series of (E)- and (Z)-[[[2-(1H-imidazol-1-yl)ethylidene]amino]oxy]pentanoic acids showed relevant thromboxane synthase inhibition associated with weak TxA₂ receptor antagonism, while a series of (±)-(E)-[[[2-(1H-imidazol-1-yl)-3- phenylpropylidene]amino]oxy]pentanoic acids, structurally derived from the former, showed potent and well-balanced dual activity. Structural 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 23c and its p- fluorophenyl analog 23m, inhibited TxB₂ production in vitro, in rat whole blood during clotting, with IC₅₀ of 0.06 and 0.37 μM and antagonized the binding of [³H]SQ 29548 to washed human platelets, with IC₅₀ of 0.08 and 0.02 μM, respectively. These two compounds were selected for further pharmacological evaluation and were shown to antagonize U46619-induced platelet aggregation in human platelet rich plasma with IC₅₀ of 0.30 and 0.44 μM, respectively. They were both orally available, and in particular 23m caused a long lasting ex vivo TxA₂ synthase inhibition in the fed rat. The levorotatory enantiomer of 23c, stereospecifically synthesized as a model compound, was found to be more potent than racemic 23c with regard to TxA₂ receptor antagonism (IC₅₀ = 0.04 μM) and equivalent to the latter with regard to TxA₂ synthase inhibition. A molecular modeling study concerning the levorotatory enantiomer of 23c (S), TxA₂, and representative TxA₂ antagonists of different classes led to the definition of a putative pharmacophoric model for the TxA₂ receptor ligands.