Butenolide endothelin antagonists with improved aqueous solubility.

Continued development around our ETA-selective endothelin (ET) antagonist 1 (CI-1020) has led to the synthesis of analogues with improved aqueous solubility profiles. Poor solubility characteristics displayed by 1 required a complex buffered formulation in order to conduct iv studies. To overcome the use of specific iv formulations for preclinical studies on additional drug candidates, analogues with improved aqueous solubility were desired. Several analogues were synthesized with substitution patterns that allowed for the formation of either acid or base addition salts. These derivatives had dramatically improved aqueous solubility. In addition, these analogues retained equivalent or improved ETA receptor selectivity and antagonist potency, versus 1, both in vitro and in vivo. Compound 29, which contains as a substituent the sodium salt of a sulfonic acid, has an ETA IC50 = 0.38 nM, ETA selectivity of 4200-fold, and ETA functional activity of KB = 7.8, all of which are similar or superior to those of 1. Compound 29 also has vastly superior aqueous solubility and solubility duration, compared to 1. Furthermore, 29 after iv infusion displays improved activity to 1 in preventing acute hypoxia-induced pulmonary hypertension in rats with an ED50 = 0.3 microg/kg/h.

Structure-activity relationships in a series of orally active gamma-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 ETA selective antagonists. Starting from a micromolar screening hit, PD012527, use of Topliss decision tree analysis led to the discovery of the nanomolar ET(A) selective antagonist PD155080. Further structural modifications around the butenolide ring led directly to the subnanomolar ETA selective antagonist PD156707, IC50's = 0.3 (ET(A)) and 780 nM (ET(B)). This series of compounds exhibited functional activity exemplified by PD156707. This derivative inhibited the ETA receptor mediated release of arachidonic acid from rabbit renal artery vascular smooth muscle cells with an IC50 = 1.1 nM and also inhibited the ET-1 induced contraction of rabbit femoral artery rings (ETA mediated) with a pA2 = 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 gamma-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.

Structure-activity relationships of a novel series of orally active nonpeptide ETA and ETA/B endothelin receptor-selective antagonists.

The development of nonpeptide, low molecular weight antagonists with high potency, oral activity, and selectivity is an important objective to adequately define the potential role of endothelin (ET) and its isopeptides in human diseases. This report describes the structure-activity relationships, ETA/ETB selectivity, and pharmacokinetics of the PD 155080 and PD 156707 series of orally active nonpeptide ET receptor-selective antagonists. Modification of the substituents around the butenolide ring has led to compounds with differing selectivity for human ETA and ETB receptors. Thus, compounds with increased lipophilicity at R2 show increased ETB affinity and a more balanced ETA/ETB profile. For example, the 4-O-n-pentyl analogue of PD 156707 is a potent competitive inhibitor of [125I]ET-1 and [125I]ET-3 binding to human cloned ETA and ETB receptors, with IC50s of 0.8 nM and 44 nM, respectively. Pharmacokinetic properties can also be significantly influenced by structural modifications at the R2 group. The pharmacokinetics of PD 155719, PD 155080, and PD 156707 were compared in male Wistar rats after a 15 mg/kg intravenous or oral gavage dose (three animals per dose). Plasma concentrations were determined by a specific HPLC assay. Oral bioavailability ranged from less than 5% for PD 155719 to 41% for PD 156707 and 87% for PD 155080.