New nonpeptide angiotensin II receptor antagonists. 1. Synthesis, biological properties, and structure-activity relationships of 2-alkyl benzimidazole derivatives.
On the basis of an extension of the literature lead 1, a series of benzimidazoles have been synthesized and shown to be angiotensin II (AII) receptor antagonists. The structure-activity relationships of these new antagonists have been explored and the key binding interactions defined. Molecular mechanics calculations were carried out on analogues of imidazole AII antagonists and conformationally restricted analogues were synthesized. The benzimidazole antagonists displaced AII in binding studies in vitro with IC50 values in the range 10(-5)-10(-7) M and antagonized the hypertensive effects of AII in vivo (rats) following intravenous administration with ED50 values in the range of 5-20 mg/kg.
Thomas
A P
AP
Department of Chemistry, ICI Pharmaceuticals, Macclesfield, Cheshire, U.K.
Allott
C P
CP
Gibson
K H
KH
Major
J S
JS
Masek
B B
BB
Oldham
A A
AA
Ratcliffe
A H
AH
Roberts
D A
DA
Russell
S T
ST
Thomason
D A
DA
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D006168:Guinea Pigs; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D000804:Angiotensin II