New nonpeptide angiotensin II receptor antagonists. 2. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)quinoline derivatives.
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.
Bradbury
R H
RH
Department of Chemistry, ICI Pharmaceuticals, Macclesfield, Cheshire, U.K.
Allott
C P
CP
Dennis
M
M
Fisher
E
E
Major
J S
JS
Masek
B B
BB
Oldham
A A
AA
Pearce
R J
RJ
Rankine
N
N
Revill
J M
JM
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
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D011804:Quinolines; D011945:Receptors, Angiotensin; D000804:Angiotensin II