2-butyl-3-({4-[2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

• ChemBase ID: 901
• Molecular Formular: C25H28N6O
• Molecular Mass: 428.52942
• Monoisotopic Mass: 428.23245955
• SMILES: O=C1N(C(=NC21CCCC2)CCCC)Cc1ccc(cc1)c1c(cccc1)c1n[nH]nn1
• Canonical SMILES: CCCCC1=NC2(C(=O)N1Cc1ccc(cc1)c1ccccc1c1n[nH]nn1)CCCC2
• InChI: InChI=1S/C25H28N6O/c1-2-3-10-22-26-25(15-6-7-16-25)24(32)31(22)17-18-11-13-19(14-12-18)20-8-4-5-9-21(20)23-27-29-30-28-23/h4-5,8-9,11-14H,2-3,6-7,10,15-17H2,1H3,(H,27,28,29,30)
• InChIKey: YOSHYTLCDANDAN-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 2-butyl-3-({4-[2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1,3-diazaspiro[4.4]non-1-en-4-one; 2-butyl-3-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1,3-diazaspiro[4.4]non-1-en-4-one
• IUPAC Traditional name: avapro; 2-butyl-3-({4-[2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1,3-diazaspiro[4.4]non-1-en-4-one; irbesartan
• Brand Name: Avalide; Avapro; Irbesarran; Irbesartan [Usan:Inn]; Lrbesartan
• Synonyms: 3-((2'-(1H-Tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)-methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one; 2-Butyl-3-[[2′-(2H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one; Avapro; Irbesartan; 3-((2'-(1H-Tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one; 2-Butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one; irbesartan; Irbesartan; BMS-186295; SR-47436; Aprovel; Karvea; Irbesartan(Avapro)

Database IDs

• CAS Number: 138402-11-6
• MDL Number: MFCD00864464
• PubChem SID: 160964364; 46506575
• PubChem CID: 3749

CALCULATED PROPERTIES

JChem

• Acid pKa: 7.3994555
• H Acceptors: 5
• H Donor: 1
• LogD (pH = 5.5): 5.4726286
• LogD (pH = 7.4): 5.2058716
• Log P: 5.495262
• Molar Refractivity: 136.7161 cm^3
• Polarizability: 49.200542 Å^3
• Polar Surface Area: 87.13 Å^2
• Rotatable Bonds: 7
• Lipinski's Rule of Five: false

ALOGPS 2.1

• Log P: 4.51
• LOG S: -4.69
• Solubility (Water): 8.84e-03 g/l

PROPERTIES

Physical Property

• Solubility: DMSO: >25 mg/mL; Ethanol; Methanol
• Apperance: White Solid; white to off-white powder
• Melting Point: 180-181°C
• Hydrophobicity(logP): 6

Safety Information

• Storage Condition: -20°C; -20°C Freezer
• Storage Warning: IRRITANT
• German water hazard class: 3
• TSCA Listed: false
• Storage Temperature: 2-8°C

Pharmacology Properties

• Target: Angiotensin receptor
• Mechanism of Action: Angiotensin II AT 1 -receptor antagonist

Product Information

• Purity: ≥98% (HPLC); 95+%
• Salt Data: Free Base
• Application(s): Antihypertensive agent
• Empirical Formula (Hill Notation): C25H28N6O

DETAILS

DrugBank - DB01029

• Drug Groups: approved; investigational
• Description: Irbesartan is an angiotensin receptor blocker (ARB) used mainly for the treatment of hypertension. It competes with angiotensin II for binding at the AT1 receptor subtype. Unlike ACE inhibitors, ARBs do not have the adverse effect of dry cough. The use of ARBs is pending revision due to findings from several clinical trials suggesting that this class of drugs may be associated with a small increased risk of cancer.
• Indication: For the treatment of hypertension, as well as diabetic nephropathy with an elevated serum creatinine and proteinuria (>300 mg/day) in patients with type 2 diabetes and hypertension. Irbesartan is also used as a second line agent in the treatment of congestive heart failure.
• Pharmacology: Angiotensin II, the principal pressor agent of the renin-angiotensin system, is responsible for effects such as vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Irbesartan is a specific competitive antagonist of AT₁ receptors with a much greater affinity (more than 8500-fold) for the AT₁ receptor than for the AT₂ receptor and no agonist activity. Irbesartan's inhibition of angiotensin II binding to the AT1 receptor leads to multiple effects including vasodilation, a reduction in the secretion of vasopressin, and reduction in the production and secretion of aldosterone. The resulting effect is a decrease in blood pressure.
• Toxicity: Hypotension and tachycardia; bradycardia might also occur from overdose, LD₅₀=mg/kg(orally in rat)
• Affected Organisms: Humans and other mammals
• Biotransformation: Hepatic. Irbesartan is metabolized via glucuronide conjugation and oxidation. In vitro studies of irbesartan oxidation by cytochrome P450 isoenzymes indicated irbesartan was oxidized primarily by 2C9; metabolism by 3A4 was negligible.
• Absorption: Rapid and complete with an average absolute bioavailability of 60-80%. Food has no affect on bioavailability.
• Half Life: 11-15 hours
• Protein Binding: 90% bound to serum proteins (primarily albumin and a1-acid glycoprotein) with negligible binding to cellular components of blood.
• Elimination: Irbesartan is metabolized via glucuronide conjugation and oxidation. Irbesartan and its metabolites are excreted by both biliary and renal routes. Irbesartan is excreted in the milk of lactating rats.
• Distribution: * 53 to 93 L
• Clearance: * 157-176 mL/min
• References: Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001 Sep 20;345(12):851-60. [Pubmed] ; Adams MA, Trudeau L: Irbesartan: review of pharmacology and comparative properties. Can J Clin Pharmacol. 2000 Spring;7(1):22-31. [Pubmed] ; Croom KF, Curran MP, Goa KL, Perry CM: Irbesartan: a review of its use in hypertension and in the management of diabetic nephropathy. Drugs. 2004;64(9):999-1028. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Selleck Chemicals - S1507

Research Area

• Description: Cardiovascular Disease

Biological Activity

• Description: 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.
• Targets: AT1
• IC50: 1.3 nM ^[1]
• In Vitro: 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 α_v, 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]
• In Vivo: 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]
• Clinical Trials: 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.
• Features: Irbesartan is a longer acting AT1 receptor antagonist than losartan and valsartan.

Protocol

• Protocol: Kinase Assay ^[1]
• 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.
• Protocol: Animal Study ^[1]
• 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

References

• References: [1] Bernhart CA, et al. J Med Chem, 1993, 36(22), 3371-3380.
• References: [2] Kawano H, et al. Hypertension, 2000, 35, 273-279.
• References: [3] Schupp M, et al. Circulation, 2004, 109(17), 2054-2057.
• References: [4] Ruiz E, et al. Eur J Pharmacol, 2007, 567(3), 231-239.
• References: [5] Dalla Libera L, et al. Circulation, 2001, 103(17), 2195-2200.

Sigma Aldrich - I2286

Biochem/physiol Actions
Irbesartan is an angiotensin II type 1 (AT1) receptor antagonist with anti-hypertensive activity.

Toronto Research Chemicals - I751000

An angiotensin II type 1 (AII1)-receptor antagonist.

REFERENCES

• Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001 Sep 20;345(12):851-60. Pubmed
• Adams MA, Trudeau L: Irbesartan: review of pharmacology and comparative properties. Can J Clin Pharmacol. 2000 Spring;7(1):22-31. Pubmed
• Croom KF, Curran MP, Goa KL, Perry CM: Irbesartan: a review of its use in hypertension and in the management of diabetic nephropathy. Drugs. 2004;64(9):999-1028. Pubmed
• Bernhart CA, et al. J Med Chem, 1993, 36(22), 3371-3380.
• Kawano H, et al. Hypertension, 2000, 35, 273-279.
• Schupp M, et al. Circulation, 2004, 109(17), 2054-2057.
• Ruiz E, et al. Eur J Pharmacol, 2007, 567(3), 231-239.
• Dalla Libera L, et al. Circulation, 2001, 103(17), 2195-2200.
• Gillis, J.C. and Markham, A.: Drugs, 54, 885 (1997)
• Chando, T.J., et al.: Drug. Metabol. Dispos., 26, 408 (1997)
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• Gillis, J.C. et al., Drugs, 1997, 54, 885-902, (pharmacol, rev)
• Bckei, Z. et al., Acta Cryst. C, 1998, 54, 808-810, (desmotropic forms, cryst. struct)
• Chando, T.J. et al., Drug Metab. Dispos., 1998, 26, 408-417, (metab)
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