New nonpeptide angiotensin II receptor antagonists. 3. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)pyridine derivatives

Abstract

A novel series of nonpeptide angiotensin II (AII) receptor antagonists is reported, derived from linkage of the biphenylyltetrazole moiety found in previously described antagonists via a methyleneoxy chain to the 4-position of a 3-substituted 2,6-dialkylpyridine. 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 0.005-0.5 microM. A variety of substituents was found to be effective at the 3-position of the pyridine ring. On intravenous administration in a normotensive rat model, the more potent compounds inhibited the AII-induced pressor response with ED50 values in the range 0.1-1.0 mg/kg. One of the compounds, 2-ethyl-5,6,7,8-tetrahydro-4-([2'-(1H-tetrazol-5-yl)biphenyl-4y l] methoxy)quinoline (26), demonstrated good oral activity in two rat models. At doses in the range 1-10 mg/kg po in AII-infused, conscious, 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 26 showed a rapid and sustained lowering of blood pressure at a dose of 5 mg/kg po. Based on its profile, this compound, designated ICI D6888, has been selected for evaluation in volunteers.

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

“…The superposition used in the prediction of the ICI compound ( Fig. 9) is consistent with functional group mappings identified previously [29]. However, the relative location of the tetrazole differs in our model.…”

“…In addition, although no imidazoles were included in the training set, we were accurately able to predict the potency of DUP753 [28]. The correct estimation of the ICI compound [29] by our CoMFA analysis indicates that it falls within the spatial bounds of our analysis and does not sample any new property space, although this is not necess- arily intuitive from a 2D perspective. The superposition used in the prediction of the ICI compound ( Fig.…”

A Non-Peptide Angiotensin II Receptor Antagonist: 2-Butyl-6-dimethoxymethyl-5-phenyl-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazo[5,4-b]pyridine

“….53 (2) .49 (2) .37 (2) .42 (2) .45 (2) .32 (2) (Kubo et al, 1993); (Ellingboe et al, 1994); (IV) 2-ethyl-5,6,7,8-tetrahydro-4-{ [U-( 1H-tetrazol-5-yl)biphenyl-4-yl]methoxyl}quinolone (Bradbury et al, 1993); all the crystal structures are in centrosymmetric space groups.…”

A new class of potential antidiabetic acetohydrazides: Synthesis, in vivo antidiabetic activity and molecular docking studies

“…A series of tetrazole-chromone derivatives have been declared as anti-allergic substances (Nohara et al, 1977) while 5-(pyridyl) tetrazole derivatives are efficient lipid regulators (Holland, 1969). We know some more derivatives having tetrazole moiety are good nonpeptide angiotensin receptor antagonists (Bradbury et al, 1993), SGLT2 inhibitors (Gao et al, 2010) and superoxide scavengers (Maxwell et al, 1984). Orally active, highly potent compounds derived from the picolinaldehyde bearing tetrazole ring are mGlu5 receptor antagonist (Huang et al, 2004).…”