[Prostacyclin mimetics with non-prostanoid structures]

Abstract

In searching for new drugs, we have developed receptor binding assays for prostanoids. Among the various compounds that we have tested, we have found that hydronaphthalene derivatives can interact with some prostanoid receptors. Modification of such compounds produced several pure prostacyclin agonists (ONO-AP-227 and ONO-AP-437) and a unique prostacyclin agonist with inhibitory activity against thromboxane synthase (ONO-AP-500-02). These compounds showed specific binding to the IP receptor with Ki values less than 0.2 microM, without binding to EP and TP receptors. These compounds also inhibited human platelet aggregation with IC50 values of 0.03-0.24 microM. These compounds inhibited ex vivo platelet aggregation in dogs or rats in the dose range of 1 to 30 mg/kg. Furthermore, ONO-AP-500-02 inhibited ex vivo thromboxane formation at doses similar to those inhibiting platelet aggregation in rats. These results, taken together, suggest that chemical syntheses of compounds targeting prostanoid receptors can produce unique prostanoid agonists or antagonists, and rational syntheses might be possible for compounds with different pharmacological actions such as inhibition of thromboxane synthase.