• Journal of Life Science
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• v.20 no.7
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• pp.969-976
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• 2010

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 ($ID_{50}$: 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 ($ID_{50}$: 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 $E_{max}$: 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 $E_{max}$: 2-4 hr), as well as a 20-fold greater potency than losartan. These results suggest that KR-31125 is a potent, orally active $AT_1$ receptor antagonist that can be applied to the development of new diagnostic and research tools as an added exploratory potential of $AT_1$ receptor antagonist.

• Journal of Life Science
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• v.20 no.6
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• pp.831-837
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• 2010

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) is a potent inhibitor of angiotensin II type 1 ($AT_1$) receptors in human recombinant $AT_1$ receptors and rabbit aorta. These in vitro studies revealed that KR-31125 inhibited specific [$^{125}I$] [$Sar^1$, $Ile^8$]-angiotensin II binding to human recombinant $AT_1$ receptors in a concentration dependent manner with an $IC_{50}$ value of $19.72{\pm}2.65$ nM. However, no interaction with $AT_2$ receptors was detected as displayed by the competition binding of [$^{125}I$] CGP 42112A to human recombinant $AT_2$ receptor. The binding action was also confirmed as a competitive mode that was identical to the previously studied compound, losartan. In addition, KR-31125 caused a nonparallel shift to the right in the concentration response curves to angiotensin II with a 30-80% decrease in the maximum contractile responses ($pK_B$: 7.63). Compared to the previous studies with losartan that showed a parallel right shift in the maximum contractile responses to AII ($pA_2$: 7.59), KR-31125 presented a different mode of action with a similar potency to losartan. These results demonstrate that KR-31125 is a highly potent and $AT_1$ selective angiotensin II receptor antagonist that can be applied to the fields of new diagnostic and research tools with upcoming in vivo study results.