New nonpeptide angiotensin II receptor antagonists. 3. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)pyridine derivatives.
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.
Bradbury
R H
RH
Department of Chemistry, ZENECA Pharmaceuticals, Macclesfield, Cheshire, U.K.
Allott
C P
CP
Dennis
M
M
Girdwood
J A
JA
Kenny
P W
PW
Major
J S
JS
Oldham
A A
AA
Ratcliffe
A H
AH
Rivett
J E
JE
Roberts
D A
DA
D000311:Adrenal Glands / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D006977:Hypertension, Renal / Q000188:drug therapy; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011804:Quinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D011804:Quinolines; D000804:Angiotensin II; C081117:ICI D6888