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Research Area
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Description
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Cardiovascular Disease |
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Biological Activity
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Description
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Irbesartan (Avapro, SR-47436, BMS-186295) is a highly potent and specific angiotensin II type 1 (AT1) receptor antagonist with IC50 of 1.3 nM. |
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Targets
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AT1 |
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IC50 |
1.3 nM [1] |
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In Vitro
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Irbesartan competes with angiotensin II (AII) for binding at the AT1 receptor subtype and antagonizes AII-induced contraction in rabbit aorta ring with IC50 of 4 nM. Irbesartan has no affinity for AT2 receptors. [1] Irbesartan (10 μM) blocks angiotensin II induced increase in αv, β1, β3, and β5 integrins, osteopontin, and α-actinin mRNA and protein levels in rat cardiac fibroblasts, leading to the decrease of cell attachment to extracellular matrix (ECM) proteins. [2] Irbesartan treatment markedly induces the expression of the adipogenic marker gene adipose protein 2 (aP2) in 3T3-L1 cells in a concentration-dependent manner with EC50 of 3.5 μM and 3.3-fold induction at the concentration of 10 μM. Irbesartan (10 μM) markedly induces transcriptional activity of the peroxisome proliferator–activated receptor-γ (PPARγ) by 3.4-fold independent of its AT1 receptor blocking action. [3] Pretreatment with Irbesartan (~10 μM) decreases angiotensin II-induced apoptosis in rat vascular smooth muscle cells by blocking angiotensin II internalization in a concentrationdependent manner. [4] |
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In Vivo
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Oral administration of Irbesartan (1 mg/kg) reduces angiotensin II (AII)-induced hypertension, equipotent with losartan in conscious normotensive rats, markedly more active than losartan (10 mg/kg) in normotensive cynomolgus monkeys. [1] Administration of Irbesartan (7 mg/kg/day) significantly prevents skeletal muscle apoptosis and muscle atrophy in rats with monocrotaline-induced congestive heart failure (CHF), which is involved with the decrease of TNFα level and attributed to AT1 receptor blocking. [5] |
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Clinical Trials
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A Phase I study to evaluate pharmacokinetics and safety after oral administration of Irbesartan and Atorvastatin in combination as HCP0912 in healthy male subjects has been completed. |
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Features
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Irbesartan is a longer acting AT1 receptor antagonist than losartan and valsartan. |
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Protocol
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Kinase Assay
[1]
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| Angiotensin II Binding Study on Rat Liver Membranes |
The plasma membranes of livers are purified from male Sprague-Dawley rats, and diluted in the incubation buffer (20 mM Tris-HCI, 10 mM MgCI2, 2 g/L RSA, 145 mg/L bacitracin, pH 7.5). Aliquots of membrane suspension (20-330 μg protein/assay) are incubated for 1 hour at 25 °C with [125I]angiotensin II (AII) and various concentrations of Irbesartan in 200 μL of incubation buffer. The incubation is stopped by rapid filtration through a Whatman GF/B filter followed by three consecutive washing sin 5 mL of cold incubation buffer (the GF/B filters are preincubated for 1 hour in the incubation buffer). The radioactivity bound to the filter is counted in a γ counter. Specific binding is defined as the difference between total binding and the binding in the presence of 1 μM unlabeled angiotensin II (AII). The concentration of Irbesartan producing 50% inhibition (IC50) of radioligand binding is determined from competition curve. |
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Animal Study
[1]
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| Animal Models |
Male Sprague-Dawley rats and female cynomolgus monkeys (Macaca fascicularis) injected (iv) with angiotensin II (AII) |
| Formulation |
Dissolved in water by neutralization with a stoichiometric equivalent of KOH, or dissolved in saline by neutralization with a stoichiometric equivalent of L-arginine |
| Doses |
1 mg/kg |
| Administration |
Oral gavage |
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References |
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[1] Bernhart CA, et al. J Med Chem, 1993, 36(22), 3371-3380.
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[2] Kawano H, et al. Hypertension, 2000, 35, 273-279.
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[3] Schupp M, et al. Circulation, 2004, 109(17), 2054-2057.
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[4] Ruiz E, et al. Eur J Pharmacol, 2007, 567(3), 231-239.
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[5] Dalla Libera L, et al. Circulation, 2001, 103(17), 2195-2200.
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