title: 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.
authors.affiliation: Department of Chemistry, ICI Pharmaceuticals, Macclesfield, Cheshire, U.K.
authors.forename: R H
authors.initials: RH
authors.lastname: Bradbury
authors.forename: C P
authors.initials: CP
authors.lastname: Allott
authors.forename: M
authors.initials: M
authors.lastname: Dennis
authors.forename: E
authors.initials: E
authors.lastname: Fisher
authors.forename: J S
authors.initials: JS
authors.lastname: Major
authors.forename: B B
authors.initials: BB
authors.lastname: Masek
authors.forename: A A
authors.initials: AA
authors.lastname: Oldham
authors.forename: R J
authors.initials: RJ
authors.lastname: Pearce
authors.forename: N
authors.initials: N
authors.lastname: Rankine
authors.forename: J M
authors.initials: JM
authors.lastname: Revill
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006860:Hydrogen Bonding; D006977:Hypertension, Renal / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011945:Receptors, Angiotensin / Q000378:metabolism; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D011804:Quinolines; D011945:Receptors, Angiotensin; D000804:Angiotensin II