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.

Continued SAR around our ETA selective series of butenolide antagonists, for example PD156707 (1) has yielded a new series of subnanomolar ETA selective antagonists. Depending upon solution pH, 1 exists as the ring closed butenolide form (shown) or as the tautomeric open chain keto-acid salt. Reaction of the butenolide γ-hydroxyl with isocyanates yields carbamates with essentially identical ETA binding affinity and with improved ETA selectivity. As carbamates these derivatives may undergo facile hydrolysis, reverting back to their parent butenolides, and therefore may be useful as prodrugs of 1. Stability studies of PD163140 (7) indicate that the compound is stable in the binding assay conditions and hence has intrinsic activity. In addition 7 is readily hydrolyzed by rat intestinal perfusate to yield the parent compound 1.

The endothelins (ETs) are a family of bicyclic 21-amino acid peptides that are potent and prolonged vasoconstrictors. It has been shown that highly potent combined ETA/ETB receptor antagonists can be developed from the C-terminal hexapeptide of ET (His16-Leu17-Asp18-Ile19-Ile20-Trp21), such as Ac-(D)Dip16-Leu-Asp-Ile-Ile-Trp21 (PD 142893) and Ac-DBhg16-Leu-Asp-Ile-Ile-Trp21 (PD 145065). However, these compounds are relatively unstable to enzymatic proteolysis as determined in an in vitro rat intestinal perfusate assay. This instability is thought to be due to carboxypeptidase activity. In fact, incubation of PD 145065 with carboxypeptidase inhibitors greatly increased its half-life in rat intestinal perfusate. By performing a reduced amide bond and N-methyl amino acid scan, it was discovered that N-methylation of Ile-20 resulted in a compound (Ac-DBhg16-Leu-Asp-Ile-[NMe]Ile-Trp21, PD 156252) that retained full receptor affinity at both endothelin receptor subtypes along with enhanced proteolytic stability and cellular permeability. Interestingly, N-methylation of this bond allows the cis configuration to be readily accessible which greatly alters the preferred structure of the entire molecule and may be responsible for the observed enhanced metabolic stability.

Endothelin-1 is a potent vasoconstrictor which is thought to be involved in many human disease states. We have developed a series of indole non-peptide endothelin antagonists which display nanomolar receptor affinity. The representative compound from this series is PD 159433 (22), an ETA selective antagonist with an IC50 of 2 nM. The discovery, synthesis and structure-activity relationships of this series of compounds are described.

Endothelin-1 is a potent vasoconstrictor that is thought to be involved in many human disease states. We have developed a series of indole non-peptide endothelin antagonists including PD 159110 (31), an ETA selective antagonist, and PD 159020 (37), a non-selective ETA/ETB antagonist. The discovery, synthesis, and structure-activity relationships of this series of compounds are described.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDiscovery of a Novel Series of Orally Active Non-Peptide Endothelin-A (ETA) Receptor-Selective AntagonistsAnnette M. Doherty, William C. Patt, Jeremy J. Edmunds, Kent A. Berryman, Billy R. Reisdorph, Mark S. Plummer, Aurash Shahripour, Chet Lee, Xue-Min Cheng, and Cite this: J. Med. Chem. 1995, 38, 8, 1259–1263Publication Date (Print):April 1, 1995Publication History Published online1 May 2002Published inissue 1 April 1995https://pubs.acs.org/doi/10.1021/jm00008a002https://doi.org/10.1021/jm00008a002research-articleACS PublicationsRequest reuse permissionsArticle Views379Altmetric-Citations98LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (3)»Supporting Information Supporting Information Get e-Alerts

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.

The endothelins (ETs) are a family of bicyclic 21-amino acid-containing peptides that are highly potent and prolonged vasoconstrictors. The discovery of potent ET antagonists will facilitate the understanding of the physiological and/or pathophysiological role of ET. Structure-activity studies have revealed the importance of the C-terminal hexapeptide (residues 16-21) of ET (His16-Leu17-Asp18-Ile19-Ile20-Trp21) to the development of potent antagonists at both receptor subtypes (ETA and ETB). In particular, it has been shown that Ac-DDip16-Leu-Asp-Ile-Ile-Trp21 (Dip = 3,3-diphenylalanine) has low nanomolar affinity for the two endothelin receptor subtypes and is a functional antagonist of ET activity, both in vitro and in vivo at both receptors. Herein, we will describe the structure-activity relationships of Ac-DDip16-Leu-Asp-Ile-Ile-Trp21 (PD 142893) with a particular emphasis on modifications that lead to enhanced receptor affinity and/or individual receptor subtype selectivity. In particular, we will demonstrate how we utilized PD 142893 to develop ETB receptor selective ligands and the pharmacological differences that exist between species ETB receptors with respect to their affinity for C-terminal hexapeptide antagonists.

We describe the pharmacological characteristics of PD 156707 (sodium 2-benzo[1,3]dioxol-5-yl-4-(4-methoxy-phenyl)-4-oxo-3-(3,4,5- trimethoxy-benzyl)-but-2-enoate), a potent, orally active, nonpeptide antagonist of the endothelin A (ETA) receptor subtype. PD 156707 was designed on the basis of a compound identified by screening the Parke-Davis chemical library. PD 156707 is highly selective for the ETA receptor (ETAR) and inhibits the binding of [125I]-ET-1 to cloned human ETAR and ETBR with Ki values of 0.17 and 133.8 nM, respectively. PD 156707 antagonizes ET-1-stimulated phosphoinositide hydrolysis in Ltk- cells expressing cloned human ETAR with an IC50 value of 2.4 nM. PD 156707 inhibits vasoconstriction in isolated blood vessels mediated by ETAR (rabbit femoral artery) and ETBR (rabbit pulmonary artery) with pA2 values of 7.5 and 4.7, respectively. PD 156707 administered orally to rats blocked subsequent ETAR-mediated pressor responses in vivo but had no effect on ETBR-mediated dilator responses. As a potent and orally active ETA-selective antagonist, PD 156707 will be useful in defining the physiological and pathological roles of ETAR.