Structure−Activity Relationships in a Series of Orally Active γ-Hydroxy Butenolide Endothelin Antagonists

The design of potent and selective non-peptide antagonists of endothelin-1 (ET-1) and its related isopeptides are important tools defining the role of ET in human diseases. In this report we will describe the detailed structure−activity relationship (SAR) studies that led to the discovery of a potent series of butenolide ET<INF>A</INF> selective antagonists. Starting from a micromolar screening hit, PD012527, use of Topliss decision tree analysis led to the discovery of the nanomolar ET<INF>A</INF> selective antagonist PD155080. Further structural modifications around the butenolide ring led directly to the subnanomolar ET<INF>A</INF> selective antagonist PD156707, IC<INF>50</INF>'s = 0.3 (ET<INF>A</INF>) and 780 nM (ET<INF>B</INF>). This series of compounds exhibited functional activity exemplified by PD156707. This derivative inhibited the ET<INF>A</INF> receptor mediated release of arachidonic acid from rabbit renal artery vascular smooth muscle cells with an IC<INF>50</INF> = 1.1 nM and also inhibited the ET-1 induced contraction of rabbit femoral artery rings (ET<INF>A</INF> mediated) with a pA<INF>2</INF> = 7.6. PD156707 also displayed in vivo functional activity inhibiting the hemodynamic responses due to exogenous administration of ET-1 in rats in a dose dependent fashion. Evidence for the pH dependence of the open and closed tautomerization forms of PD156707 was demonstrated by an NMR study. X-ray crystallographic analysis of the closed butenolide form of PD156707 shows the benzylic group located on the same side of the butenolide ring as the γ-hydroxyl and the remaining two phenyl groups on the butenolide ring essentially orthogonal to the butenolide ring. Pharmacokinetic parameters for PD156707 in dogs are also presented.