New nonpeptide angiotensin II receptor antagonists. 2. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)quinoline derivatives

Abstract

A novel series of nonpeptidic angiotensin II (AII) receptor antagonists is reported, derived from linkage of the biphenylcarboxylic acid or biphenylyltetrazole moiety found in previously described antagonists via a methyleneoxy chain to the 4-position of a 2-alkyl quinoline. When evaluated in an in vitro binding assay using a guinea pig adrenal membrane preparation, compounds in this series generally gave IC50 values in the range 0.01-1 microM. Structure-activity studies showed the quinoline nitrogen atom and a short alkyl chain at the quinoline 2-position to be essential for receptor binding. On intravenous administration in a normotensive rat model, the more potent compounds inhibited the AII-induced pressor response with ED50 values in the range 0.1-2.0 mg/kg. One of the compounds, 2-ethyl-4-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methoxy]quinoline (5g), demonstrated good oral activity in two rat models. At doses in the range 1-10 mg/kg in AII-infused, normotensive rats, the compound exhibited a dose-related inhibition of the pressor response with a good duration of action at the higher doses. In a renal hypertensive rat model, compound 5g showed a rapid and sustained lowering of blood pressure at a dose of 5 mg/kg. On the basis of its profile, this compound, designated ICI D8731, has been selected for clinical evaluation.

Superimposition of potent non-peptide AT1 receptor antagonists with angiotensin II

“…The two rings of the biphenyl moiety of the molecule were found to prefer a twisted conformation. Such a conformation is consistent with a subsequently reported crystallographic structure of EXP7711, an o-carboxyl acid analogue of losartan [38]. The molecule adopts a V-shape with the otetrazole group folded back towards the n-butyl group.…”

Derivation of a 3D pharmacophore model for the angiotensin-II site one receptor

“…(Note that only four out of 12 750 initial conformers of L-158809 need to be considered with regard to the receptor-bound conformation when the final OMAP is imposed.) Other workers have attempted to describe the conformation of antagonists bound to A-II [23]. The conformation we chose to carry through the CoMFA analysis resembles the 'Helix 1' (H1) geometry with regard to the heterocycle-phenyl torsions [23d].…”

Insight into the Structural Requirement of 2-Alkyl-4-(biphenylmethoxy)quinolines as Nonpeptide Angiotensin II Receptor Antagonists: A QSAR Approach

“…The Ang II receptor antagonistic activity data of 2-alkyl 4-(biphenylylmethoxy)quinolines were taken from the reported work of Bradbury et al [8] (Table 1). The biological activity data (IC 50 in µM) was converted to negative logarithmic mole dose (pIC 50 ) for quantitative structure activity relationship (QSAR) analysis.…”