BIOMAT Database Logo BIOMAT Database Logo

New nonpeptide angiotensin II receptor antagonists. 3. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)pyridine derivatives. 1993

R H Bradbury, and C P Allott, and M Dennis, and J A Girdwood, and P W Kenny, and J S Major, and A A Oldham, and A H Ratcliffe, and J E Rivett, and D A Roberts
Department of Chemistry, ZENECA Pharmaceuticals, Macclesfield, Cheshire, U.K.

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.

UI MeSH Term Description Entries
D006977 Hypertension, Renal Persistent high BLOOD PRESSURE due to KIDNEY DISEASES, such as those involving the renal parenchyma, the renal vasculature, or tumors that secrete RENIN. Hypertensions, Renal,Renal Hypertension,Renal Hypertensions
D008297 Male Males
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D008968 Molecular Conformation The characteristic three-dimensional shape of a molecule. Molecular Configuration,3D Molecular Structure,Configuration, Molecular,Molecular Structure, Three Dimensional,Three Dimensional Molecular Structure,3D Molecular Structures,Configurations, Molecular,Conformation, Molecular,Conformations, Molecular,Molecular Configurations,Molecular Conformations,Molecular Structure, 3D,Molecular Structures, 3D,Structure, 3D Molecular,Structures, 3D Molecular
D011804 Quinolines
D001794 Blood Pressure PRESSURE of the BLOOD on the ARTERIES and other BLOOD VESSELS. Systolic Pressure,Diastolic Pressure,Pulse Pressure,Pressure, Blood,Pressure, Diastolic,Pressure, Pulse,Pressure, Systolic,Pressures, Systolic
D002462 Cell Membrane The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells. Plasma Membrane,Cytoplasmic Membrane,Cell Membranes,Cytoplasmic Membranes,Membrane, Cell,Membrane, Cytoplasmic,Membrane, Plasma,Membranes, Cell,Membranes, Cytoplasmic,Membranes, Plasma,Plasma Membranes
D005260 Female Females
D006168 Guinea Pigs A common name used for the genus Cavia. The most common species is Cavia porcellus which is the domesticated guinea pig used for pets and biomedical research. Cavia,Cavia porcellus,Guinea Pig,Pig, Guinea,Pigs, Guinea
D000311 Adrenal Glands A pair of glands located at the cranial pole of each of the two KIDNEYS. Each adrenal gland is composed of two distinct endocrine tissues with separate embryonic origins, the ADRENAL CORTEX producing STEROIDS and the ADRENAL MEDULLA producing NEUROTRANSMITTERS. Adrenal Gland,Gland, Adrenal,Glands, Adrenal

Related Publications

R H Bradbury, and C P Allott, and M Dennis, and J A Girdwood, and P W Kenny, and J S Major, and A A Oldham, and A H Ratcliffe, and J E Rivett, and D A Roberts
New nonpeptide angiotensin II receptor antagonists. 1. Synthesis, biological properties, and structure-activity relationships of 2-alkyl benzimidazole derivatives.
March 1992, Journal of medicinal chemistry,
R H Bradbury, and C P Allott, and M Dennis, and J A Girdwood, and P W Kenny, and J S Major, and A A Oldham, and A H Ratcliffe, and J E Rivett, and D A Roberts
Nonpeptide angiotensin II receptor antagonists. I. Synthesis and biological activity of pyridine derivatives.
September 1994, Chemical & pharmaceutical bulletin,
R H Bradbury, and C P Allott, and M Dennis, and J A Girdwood, and P W Kenny, and J S Major, and A A Oldham, and A H Ratcliffe, and J E Rivett, and D A Roberts
6-Substituted benzimidazoles as new nonpeptide angiotensin II receptor antagonists: synthesis, biological activity, and structure-activity relationships.
December 1993, Journal of medicinal chemistry,
R H Bradbury, and C P Allott, and M Dennis, and J A Girdwood, and P W Kenny, and J S Major, and A A Oldham, and A H Ratcliffe, and J E Rivett, and D A Roberts
Synthesis and structure-activity relationships of nonpeptide, potent triazolone-based angiotensin II receptor antagonists.
July 1993, Journal of medicinal chemistry,
R H Bradbury, and C P Allott, and M Dennis, and J A Girdwood, and P W Kenny, and J S Major, and A A Oldham, and A H Ratcliffe, and J E Rivett, and D A Roberts
Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazoles.
June 1993, Journal of medicinal chemistry,
R H Bradbury, and C P Allott, and M Dennis, and J A Girdwood, and P W Kenny, and J S Major, and A A Oldham, and A H Ratcliffe, and J E Rivett, and D A Roberts
Nonpeptide angiotensin II receptor antagonists. 1. Synthesis and in vitro structure-activity relationships of 4-[[[(1H-pyrrol-1-ylacetyl)amino]phenyl]methyl]imidazole derivatives as angiotensin II receptor antagonists.
June 1993, Journal of medicinal chemistry,
R H Bradbury, and C P Allott, and M Dennis, and J A Girdwood, and P W Kenny, and J S Major, and A A Oldham, and A H Ratcliffe, and J E Rivett, and D A Roberts
Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazolecarboxylic acids.
July 1993, Journal of medicinal chemistry,
R H Bradbury, and C P Allott, and M Dennis, and J A Girdwood, and P W Kenny, and J S Major, and A A Oldham, and A H Ratcliffe, and J E Rivett, and D A Roberts
Quinoxaline N-oxide containing potent angiotensin II receptor antagonists: synthesis, biological properties, and structure-activity relationships.
August 1993, Journal of medicinal chemistry,
R H Bradbury, and C P Allott, and M Dennis, and J A Girdwood, and P W Kenny, and J S Major, and A A Oldham, and A H Ratcliffe, and J E Rivett, and D A Roberts
Studies on nonpeptide angiotensin II receptor antagonists. IV. Synthesis and biological evaluation of 4-acrylamide-1H-imidazole derivatives.
June 1998, Chemical & pharmaceutical bulletin,
R H Bradbury, and C P Allott, and M Dennis, and J A Girdwood, and P W Kenny, and J S Major, and A A Oldham, and A H Ratcliffe, and J E Rivett, and D A Roberts
Nonpeptide angiotensin II receptor antagonists: synthesis and biological activity of 1H-imidazo and 1H-[1,2,3]-triazolo fused derivatives.
March 1997, Farmaco (Societa chimica italiana : 1989),
Copied contents to your clipboard!