Dual antagonists of the bradykinin B1 and B2 receptors based on a postulated common pharmacophore from existing non-peptide antagonists

Abstract

We have recently drawn attention to the fact that most non-peptide antagonists of the kinin B1 receptor reported so far are structurally related, possessing the core motif phenyl-SO2-NR-(spacer(2-4))-CO-NRR. This is found in compound A (N-[2-[4-(4,5-dihydro-1H-imidazol-2- yl)phenyl]ethyl] - 2- [(2R)-1-(2-napthylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetamide), a very potent and selective B1 receptor antagonist. A subset of specific bradykinin B2 receptor antagonists (LF16-0687, bradyzide and derivatives) possesses a similar 'scaffold' (phenyl-SO2-NR-CRR-CO-NRR). We investigated whether simple molecules mimicking the postulated pharmacophores could be identified in two public chemical databases. Receptor binding to B1 and B2 receptors expressed by rabbit cultured smooth-muscle cells was confirmed for some of these newly identified agents, with a loss of receptor subtype selectivity. For instance, compound 3[2-(3-oxo-1-(toluene-4-sulfonyl)-1,2,3,4-4H-quinoxalin-2-yl)-N-phenyl-acetamide] exhibits IC50 values of 2.13 and 126 microM in the radioligand competition assays for B1 and B2 receptors, respectively, and a pA2 of 6.27 at the rabbit B1 receptor in a functional test (Lys-des-Arg9-bradykinin-induced contractility of the isolated aorta). Compound 5 (a close analog of compound 3) is a more balanced dual antagonist of low potency (IC50 values of 30 and 117 microM, respectively). As predicted, compounds modeled on a postulated pharmacophore common to some non-peptide B1 or B2 receptor antagonists exhibit measurable binding with decreased receptor subtype selectivity. Dual B1/B(2) receptor antagonists are of possible therapeutic interest and should be developed.