Nonpeptide angiotensin II receptor antagonists. III. Structure-function studies.
A series of 1-benzylimidazole-5-acetate derivatives defining the critical substituents on the phenyl ring was synthesized in order to improve on the affinity of 2-butyl-4-chloro-1-(2-nitrobenzyl)imidazole-5-acetate, sodium (S-8308) for the angiotensin II (AII) receptor. The analogs, substituted with -1-(4-carboxybenzyl) (EXP6155),-1-[4-(2-carboxybenzamido)benzyl] (EXP6159) and the 5-methylacetate of EXP6159 (EXP6803), were found to inhibit the binding of [3H]AII to AII receptors in rat adrenal cortical microsomes with 9-, 35- and 107-fold higher affinity, respectively, than that of S-8308 (IC50, 15 X 10(-6) microM). Scatchard analysis of the [3H]AII binding revealed that in the presence of EXP6155 (10(-6) M), the dissociation constant for AII was increased from 1.2 to 3.9 X 10(-9) M, whereas the total number of binding sites remained unchanged, suggesting a competitive nature of antagonism. A similar order of affinity or potency (saralasin much greater than EXP6803 greater than EXP6159 greater than EXP6155 greater than S8308) was observed in various in vitro and in vivo assays: rat smooth muscle cells AII binding, 45Ca++ influx in rat aortic rings, contractile response in isolated rabbit aorta and AII-induced pressor response in anesthetized rats. Responses (45Ca++ and contraction) elicited by norepinephrine or by KCl were unaltered by these agents at concentrations of up to 10(-4) M. In addition, they exerted no direct effect on the activity of rabbit angiotensin converting enzyme and rat renin. In conscious renal artery-ligated rats, EXP6155, EXP6159 and EXP6803 were p.o. inactive, but caused a rapid decrease in mean arterial pressure when administered i.v.(ABSTRACT TRUNCATED AT 250 WORDS)
Medical Products Department, E.I. du Pont de Nemours & Company, Wilmington, Delaware.
A T
AT
Chiu
J V
JV
Duncia
D E
DE
McCall
P C
PC
Wong
W A
WA
Price
M J
MJ
Thoolen
D J
DJ
Carini
A L
AL
Johnson
P B
PB
Timmermans
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents; D002118:Calcium / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011945:Receptors, Angiotensin / Q000187:drug effects*; D012504:Saralasin / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014666:Vasomotor System / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D007093:Imidazoles; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C059699:EXP6803; C058909:S 8308; C059698:EXP6155; D012504:Saralasin; D002118:Calcium