Key result
AT1 antagonist KR-31125 lowers blood pressure faster and more potently than losartan in animal models.
Why the study?
KR-31125, a newly developed orally active AT1 receptor antagonist, required in vivo validation of its pharmacological profile compared to losartan in animal models.
Effect estimate: ID50: 0.095 mg/kg
p-value: p=<0.05
KR-31125 is a potent, orally active AT1 receptor antagonist with a more rapid onset and greater potency than losartan in animal models, showing potential as a diagnostic and research tool.
피리딜 이미다졸 시리즈의 비펩타이드 안지오텐신 수용체 리간드로 새롭게 개발된 KR-31125에 대한 생체 내활성을 동물모델에서 검증하였다. 척수장애 동물모델에서 KR-31125는 비대칭 농도의존적으로 로자탄보다 18배 이상의 경쟁적인 혈압강하 효과를 나타내었으며, 기타 수용체 촉진제들의 영향을 받지 않았다. 안지오텐신으로 유도된 정상혈압 쥐모델에서는 대조화합물인 로자탄과 비교하여 경구효과는 동등하였으나 더 빠른 초기효과가 관찰되었다. 또한 신성고혈압 쥐모델에서 KR-31125는 로자탄보다 3배 이상의 지속형 혈압강하 효과를 나타내었고, 이뇨제를 투여하여 레닌을 활성화시킨 개실험 모델에서 KR-31125는 로자탄보다 20배 이상의 지속적인 경구혈압강하 효과를 나타내었다. 이러한 KR-31125의 생체 내 활성특징은 대사물질을 통하여 효과를 발휘하는 로자탄과 달리 동일물질의 효과에 의한 것으로 고혈압 및 혈관질환과 깊은 관련이 있는 안지오텐신 조절시스템에 대한 세포영상, 비침투성 진단등의 도구물질로서 가능성이 높을 것으로 판단된다. In vivo studies of KR-31125 (2-butyl-5-dimethoxymethyl-6-phenyl-7-methyl-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine) were performed in pithed rats, conscious angiotensin II (AII) challenged normotensive rats, renal hypertensive rats (RHRs) and furosemide-treated beagle dogs. KR-31125 induced a non-parallel right shift in the dose-pressor response curve to AII ( ID₅₀ : 0.095 mg/kg) with a dose-dependent reduction in the maximum responses in pithed rats. Compared to losartan, this antagonistic effect was about 18 times more potent, presenting competitive antagonism. Other agonists such as norepinephrine and vasopressin did not alter the responses induced by KR-31125. Orally administered KR-31125 had no agonistic effect and dose-dependently inhibited the pressor response to AII with a slightly weaker potency ( ID₅₀ : 0.25 and 0.47 mg/kg, respectively) in the AII-challenged normotensive rat model, but with a more rapid onset of action than losartan (time to Eₘₐₓ : 30 min for KR-31125 and 6 hr for losartan). KR-31125 produced a dose-dependent antihypertensive effect with a higher potency than losartan in RHRs, and these effects were confirmed in furosemide-treated dogs where they presented a dose-dependent and long-lasting (>8 hr) antihypertensive effect with a rapid onset of action (time to Eₘₐₓ : 2-4 hr), as well as a 20-fold greater potency than losartan. These results suggest that KR-31125 is a potent, orally active AT₁ receptor antagonist that can be applied to the development of new diagnostic and research tools as an added exploratory potential of AT₁ receptor antagonist.
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Sung Hou Lee (2010) studied Hypertension (animal models). KR-31125 vs. Losartan or vehicle was evaluated on Inhibition of pressor response to Angiotensin II (ID50) (ID50: 0.095 mg/kg, p=<0.05). KR-31125 is a potent, orally active AT1 receptor antagonist that produced a dose-dependent and long-lasting antihypertensive effect with a more rapid onset of action and greater potency than losartan in animal models.
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