Pharmacological characterization of SR 47436, a new nonpeptide AT1 subtype angiotensin II receptor antagonist.
SR 47436, 2-n-butyl-3-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl) methyl]-1,3-diaza-spiro[4,4]non-1-en-4-one, is a new potent and selective AT1 angiotensin II (AII) receptor antagonist. It competitively inhibited [125I]AII binding to AT1 subtype receptors in rat liver membranes (IC50 = 1.7 nM) and did not interact with AT2 subtypes in rat adrenal cortical membranes. In rabbit aorta, SR 47436 inhibited contractions induced by 10 nM AII (IC50 = 4.0 nM) and shifted AII contractile response curves to the right in a parallel fashion, without total recovery of the maximal response. The potency of SR 47436 was higher than that of the lead compound, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]imidazole (DuP 753) (rat liver binding: IC50 = 16 nM; rabbit aorta: IC50 = 26 nM), and equivalent to saralasin (IC50 = 1.8 and 2.7 nM, respectively). The high specificity of SR 47436 was demonstrated by its lack of activity (IC50 > 10 microM) on various other receptors, ionic channels and antiports and rabbit aorta contracted by norepinephrine and KCl, and its lack of inhibition of renin and converting enzyme. In conscious rats, SR 47436 as well as DuP 753 (0.1 to 3 mg/kg, i.v., and 0.3 to 30 mg/kg, p.o.) antagonized the AII-pressor response in a dose-related manner. In conscious dogs, SR 47436 (1-10 mg/kg, p.o.) was a more potent antagonist of the AII pressor response than DuP 753. In conscious chronically implanted cynomolgus monkeys, SR 47436 antagonized the AII-pressor response at 1 mg/kg (89% i.v. and 66% p.o.) much more strongly than DuP 753 at 10 mg/kg (83% i.v. and 20% p.o.).(ABSTRACT TRUNCATED AT 250 WORDS)
Sanofi Recherche, Montpellier, France.
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C
Cazaubon
J
J
Gougat
F
F
Bousquet
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P
Guiraudou
R
R
Gayraud
C
C
Lacour
A
A
Roccon
G
G
Galindo
G
G
Barthelemy
B
B
Gautret
D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000378:metabolism / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D000077405:Irbesartan; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010215:Papio; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000077405:Irbesartan