PMID: 8587414Jan 1, 1995Paper

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

Journal of Cardiovascular Pharmacology
A M DohertyM A Flynn

Abstract

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....Continue Reading

Citations

Jan 1, 1996·Pharmacology & Therapeutics·G A Gray, D J Webb
May 13, 2014·Journal of Controlled Release : Official Journal of the Controlled Release Society·Anke HahnenkampCarsten Höltke
Apr 1, 1999·Annual Review of Physiology·T Miyauchi, T Masaki

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