PHARMACOLOGICAL CHARACTERIZATION OF SR-47436, A NEW NONPEPTIDE AT(1) 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 [ I-125]AII binding to AT1 subtype receptors in rat liver membranes (IC5 0 = 1.7 nM) and did not interact with AT2 subtypes in rat adrenal cort ical membranes. In rabbit aorta, SR 47436 inhibited contractions induc ed by 10 nM AII (IC50 = 4.0 nM) and shifted All contractile response c urves to the right in a parallel fashion, without total recovery of th e maximal response. The potency of SR 47436 was higher than that of th e lead compound, -(1H-tetra-zol-5-yl)biphenyl-4-yl)methyl]imidazole (D uP 753) (rat liver binding: IC50 = 16 nM; rabbit aorta: IC50 = 26 nM), and equivalent to saralasin (IC50 = 1.8 and 2.7 nM, respectively). Th e high specificity of SR 47436 was demonstrated by its lack of activit y (IC50 > 10 muM) on various other receptors, ionic channels and antip orts and rabbit aorta contracted by norepinephrine and KCl, and its la ck 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. I n conscious dogs, SR 47436 (1-10 mg/kg, p.o.) was a more potent antago nist of the AII pressor response than DuP 753. In conscious chronicall y implanted cynomolgus monkeys, SR 47436 antagonized the AII-pressor r esponse 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.). In the monkeys, SR 47436 was at least 10 times more potent than DuP 753; this result is in good ag reement with their in vitro affinity. In conclusion, SR 47436, a new c hemical structure displaying very specific and potent AT1 antagonistic properties and good oral absorption, should prove to be a promising c andidate for the treatment of hypertension and heart failure.