STRUCTURE-ACTIVITY-RELATIONSHIPS IN A SERIES OF ORALLY-ACTIVE GAMMA-HYDROXY BUTENOLIDE ENDOTHELIN ANTAGONISTS

The design of potent and selective non-peptide antagonists of endothel in-l (ET-l) and its related isopeptides are important tools defining t he role of ET in human diseases. In this report we will describe the d etailed structure-activity relationship (SAR) studies that led to the discovery of a potent series of butenolide ET(A) selective antagonists . Starting from a micromolar screening hit, PD012527, use of Topliss d ecision tree analysis led to the discovery of the nanomolar ET(A) sele ctive antagonist PD155080. Further structural modifications around the butenolide ring led directly to the subnanomolar ET(A) selective anta gonist PD156707, IC50's = 0.3 (ETA) and 780 nM (ET(B)). This series of compounds exhibited functional activity exemplified by PD156707. This derivative inhibited the ET(A) receptor mediated release of arachidon ic acid from rabbit renal artery vascular smooth muscle cells with an IC50 = 1.1 nM and also inhibited the ET-1 induced contraction of rabbi t femoral artery rings (ET(A) mediated) with a pA(2) = 7.6. PD156707 a lso displayed in vivo functional activity inhibiting the hemodynamic r esponses due to exogenous administration of ET-1 in rats in a dose dep endent 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 PD15670 7 shows the benzylic group located on the same side of the butenolide ring as the gamma-hydroxyl and the remaining two phenyl groups on the butenolide ring essentially orthogonal to the butenolide ring. Pharmac okinetic parameters for PD156707 in dogs are also presented.