Biological Activity

• Target

  Angiotensin Receptor 1 IC50:2.6nM

• DescriptionThe numerous effects of Angiotensin II (AII), including its roles in vasoconstriction, secretion of aldosterone and vasopressin, cellular proliferation, and hypertrophy are dominantly mediated through the activation of the angiotensin type 1 (AT₁) receptor, a member of the superfamily of G protein-coupled receptors. Azilsartan (AZL) is an AT₁ receptor antagonist with IC₅₀ of 2.6 nM. Pretreatment of AZL for 90 min inhibited the specific binding of ¹²⁵I-Sar¹-Ile⁸-AII to human AT₁ receptors expressed in CHO cells in a concentration-related manner with an IC₅₀ of 2.6 nM, indicating a high affinity for AT₁ receptors. A potent inhibitory effect of AZL at AT₁ receptors was maintained even 5 h after washout with an IC₅₀ value of 7.4 nM. Pretreatment of intact COS-7 cells expressing human AT₁ receptor with AZL for 2 h inhibited the accumulation of IP1 with IC₅₀ value of 9.2 nM. Pretreatment with 0.1, 0.3, or 1 nM AZL for 30 min inhibited AII-induced aortic contraction in a concentration-related manner ^[5].

• Animal Study
  Dose	Mice: 1 mg/kg - 10 mg/kg (p.o.) Rat: 10 mg/kg[3] (p.o.), 0.3 mg/kg - 3 mg/kg (p.o.)
  Administration	p.o.
  Pharmacokinetics	Animal Rats[4] Dogs[4] Monkeys[4] Dose 1 mg/kg (p.o.) 0.2 mg/kg (i.v.) 1 mg/kg (p.o.) 0.2 mg/kg (i.v.) 3 mg/kg (p.o., fasted) 0.2 mg/kg (i.v., fasted) Administration p.o. i.v. p.o. i.v. p.o. i.v. F 14.6% (p.o.) 24.3% (p.o.) 13.6% (p.o.) T1/2 5.2 h (p.o.) 2.9 h (p.o.) 1.4 h (p.o.) 1.6 h (i.v.) Cmax 0.901 μg/ml (p.o.) 0.247 μg/ml (p.o.) 0.264 μg/ml (p.o.) 3.637 μg/ml (i.v.) AUC0→24h 7.26 μg·h/ml (p.o.) 9.97 μg·h/ml (i.v.) 1.18 μg·h/ml (p.o.) 0.97 μg·h/ml (i.v.) 6.71 μg·h/ml (p.o.) 3.36 μg·h/ml (i.v.) Tmax 1.7 h (p.o.) 0.8 h (p.o.) 1.7 h (p.o.)

• Clinical Study

• NCT Number	Condition or disease	Phase	Recruitment Status	Estimated Study Completion Date	Locations
  NCT01715584	Hypertension	Phase 4	Recruiting	December 31, 2019	Canada, Ontario ... more >> London Health Sciences Centre - Victoria Campus Recruiting London, Ontario, Canada, N6A 5W9 Contact: Craig J Railton, MD, PhD    519 685 8500 ext 58525    Craig.Railton@lhsc.on.ca Principal Investigator: Craig J Railton, MD, PhD Sub-Investigator: Jonathan Fairbairn, BSc Sub-Investigator: George Nicoloau, MD Sub-Investigator: Robert Gros, PhD Sub-Investigator: Jason Franklin, MD Sub-Investigator: John Yoo, MD Sub-Investigator: Kevin Fung, MD Sub-Investigator: Anthony Nichols, MD Sub-Investigator: Danielle McNeil, MD Collapse <<
  NCT02235909	Hypertension	Phase 3	Recruiting	August 2020	-
  NCT00362115	Hypertension	Phase 2	Completed	-	-

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• References

• [1] Ojima M, Igata H, et al. In vitro antagonistic properties of a new angiotensin type 1 receptor blocker, azilsartan, in receptor binding and function studies. J Pharmacol Exp Ther. 2011 Mar;336(3):801-8.

  [2] Iwai M, Chen R, et al. TAK-536, a new AT1 receptor blocker, improves glucose intolerance and adipocyte differentiation. Am J Hypertens. 2007 May;20(5):579-86.

  [3] A9641 Novel Angiotensin II Receptor Blocker Azilsartan protects myocardium from ischemic reperfusion injury in experimental rats through Peroxisome Proliferator–Activated Receptor- γ Activation

  [4] TAK-536

  [5] Ojima M, Igata H, Tanaka M, Sakamoto H, Kuroita T, Kohara Y, Kubo K, Fuse H, Imura Y, Kusumoto K, Nagaya H. In vitro antagonistic properties of a new angiotensin type 1 receptor blocker, azilsartan, in receptor binding and function studies. J Pharmacol Exp Ther. 2011 Mar;336(3):801-8. doi: 10.1124/jpet.110.176636. Epub 2010 Dec 1. PMID: 21123673.

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