Selective endothelin A receptor ligands. 1. Discovery and structure-activity of 2,4-disubstituted benzoic acid derivatives

Article abstract of DOI:10.1016/S0223-5234(97)81678-9

This paper describes the discovery of a new non-peptide endothelin A (ET(A)) selective ligand, 2,4-dibenzyloxybenzoic acid 3, which inhibits the binding of [¹²⁵I]ET-1 to ET(A) receptors with an IC₅₀ of 9 μM (ET-1 = endothelin-1). Optimisation of 3 resulted in compound 52 which had an IC₅₀ of 1 μM. One of the analogues of 3, compound 15, was examined in a functional assay and shown to antagonise ET-1-induced contraction of rat aorta. The identification of 3 was made through the application of ChemDBS-3D searching of our corporate database. The 3D query, using an aromatic ring to a carboxylic acid group separated by 10.2 ± 1.1 A, was derived from an examination of common pharmacophoric distances found in the low energy conformations of two known ET(A) antagonists, the cyclic pentapeptide BQ 123 1 and myriceron caffeoyl ester 2.