Pharmacological properties of KT3-671, a novel nonpeptide angiotensin II receptor antagonist.
We examined pharmacological profiles of KT3-671, 2-propyl-8-oxo-1-[(2'-(1H-tetrazole-5-yl) biphenyl-4-yl)methyl]- 4,5,6,7-tetrahydro-cycloheptimidazole, a newly synthesized nonpeptide angiotensin II (AII) receptor antagonist in various in vitro and in vivo studies. KT3-671 displaced specific binding of [125I]Sar1 Ile8-AII to AT1 receptor with a Ki value of 0.71 +/- 0.14 x 10(-9) M in rat liver membranes, but had no affinity for AT2 receptor in bovine cerebellar membranes (Ki > 10(-5) M). In isolated rabbit aorta, KT3-671 produced a parallel rightward shift in the concentration-response curve for AII with a pA2 value of 10.04 +/- 0.12, but had no effect on KCl-, norepinephrine (NE)-, and serotonin (5-HT)-induced contractions. In conscious normotensive rats, KT3-671 (0.3-10 mg/kg, p.o.) inhibited the AII-induced pressor response dose dependently. In renal artery-ligated hypertensive rats, KT3-671 (0.1-3 mg/kg, p.o.) decreased arterial blood pressure (BP) dose dependently. The hypotensive action of 3 mg/kg KT3-671 was maintained for at least 24 h. These results suggest that KT3-671 is a potent AT1 subtype-selective and competitive nonpeptide AII receptor antagonist and has an orally active antihypertensive effect without agonistic activity.
Mochizuki
S
S
Research Laboratories, Kotobuki Pharmaceutical Co., Ltd., Nagano, Japan.
Sato
T
T
Furuta
K
K
Hase
K
K
Ohkura
Y
Y
Fukai
C
C
Kosakai
K
K
Wakabayashi
S
S
Tomiyama
A
A
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000378:metabolism / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006168:Guinea Pigs; D006973:Hypertension / Q000188:drug therapy; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000378:metabolism; D012077:Renal Artery / Q000187:drug effects / Q000378:metabolism; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; C093160:KT3 671; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C032651:angiotensin II, Sar(1)-Ile(5)-; D001920:Bradykinin