AT2 Agonist C21
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MedKoo CAT#: 527400

CAS#: 477775-14-7

Description: AT2 Agonist C21 is the first potent and selective agonist of angiotensin AT2 receptors, preventing endothelial inflammation and leukocyte adhesion in vitro and in vivo. AT2 Agonist C21 prevents cognitive decline after permanent stroke in aged animals-A randomized double- blind pre-clinical study. AT2 Agonist C21 attenuates pulmonary inflammation in a model of acute lung injury. AT2 Agonist C21 attenuates the Progression of Lung Fibrosis and Pulmonary Hypertension in an Experimental Model of Bleomycin-Induced Lung Injury.

Chemical Structure

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AT2 Agonist C21
CAS# 477775-14-7
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 527400
Name: AT2 Agonist C21
CAS#: 477775-14-7
Chemical Formula: C23H29N3O4S2
Exact Mass: 475.16
Molecular Weight: 475.622
Elemental Analysis: C, 58.08; H, 6.15; N, 8.83; O, 13.46; S, 13.48

Price and Availability

Size Price Availability Quantity
5mg USD 120 Ready to ship
10mg USD 190 Ready to ship
25mg USD 350 Ready to ship
50mg USD 550 Ready to ship
100mg USD 950 Ready to ship
200mg USD 1650 Ready to ship
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Synonym: AT2 Agonist C21; C21; C-21; C 21; M24; M-24; M 24; Buloxibutid; AT2 receptor agonist C21

IUPAC/Chemical Name: N-[[3-[4-(1H-Imidazol-1-ylmethyl)phenyl]-5-(2-methylpropyl)-2-thienyl]sulfonyl]carbamic acid butyl ester

InChi Key: XTEOJPUYZWEXFI-UHFFFAOYSA-N

InChi Code: InChI=1S/C23H29N3O4S2/c1-4-5-12-30-23(27)25-32(28,29)22-21(14-20(31-22)13-17(2)3)19-8-6-18(7-9-19)15-26-11-10-24-16-26/h6-11,14,16-17H,4-5,12-13,15H2,1-3H3,(H,25,27)

SMILES Code: O=C(OCCCC)NS(=O)(C1=C(C2=CC=C(CN3C=CN=C3)C=C2)C=C(CC(C)C)S1)=O

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

More Info:

Biological target: AT2 receptor agonist C21 is a druglike selective angiotensin II AT2 receptor agonist with Ki values of 0.4 nM and >10 µM for the AT2 receptor and AT1 receptor, respectively.
In vitro activity: The effect of direct AT2 receptor stimulation with Compound 21 (C21) on the leukocyte adhesion cascade in vitro was examined. Effects of C21 on TNFα-induced inflammation were assessed in human umbilical vein endothelial cells (HUVECs), activation of monocytes, and polarisation of monocyte-derived macrophages. C21 attenuated TNFα-induced: monocyte adhesion to cultured HUVECs, adhesion molecule expression and abolished TNFα-induced ROS production. TNFα-induced NFκB translocation from the cytoplasm to the nucleus, essential for cytokine production, was prevented by C21. C21 did not influence monocyte activation or macrophage polarisation but did reduce TNFα and IL-6 mRNA expression in M1 macrophages. The anti-inflammatory effects of C21 were abolished by an AT2 receptor antagonist confirming that the effects of C21 were AT2 receptor-mediated. C21 prevented TNFαinduced and HFD-induced vascular inflammation in vitro. The data provides strong evidence that the anti-atherosclerotic actions of C21 were due to vascular anti-inflammatory effects, mediated by AT2 receptors. Br J Pharmacol. 2016 Feb;173(4):729-40. https://pubmed.ncbi.nlm.nih.gov/25560767/
In vivo activity: In the present study, the role of a novel, non-peptide agonist, C21, in natriuresis via AT2 receptor activation in OZR was investigated. Infusion of C21 caused dose-dependent increases in UF (urine flow) and UNaV (urinary Na volume) relative to basal rates, and these increases were highly significant with the 5 μg kg−1 min−1 dose (Figure 2), which was used in subsequent sets of the experiment. To demonstrate that C21-induced Na excretion is mediated via the AT2 receptor, the AT2 receptor antagonist, PD123319 (50 μg kg−1 min−1 i.v.), was infused before the infusion of C21. Although PD123319 alone did not affect UF or UNaV, when compared with basal rates, it completely abolished increases in UF and UNaV in response to C21 (Figure 3), suggesting the involvement of the AT2 receptor. Infusion of C21 (5 μg kg−1 min−1) caused a significant increase in FENa (Basal: 3.033±0.9%, C21: 14.63±2.3%, P<0.05), suggesting a tubular effect of the drug (Figure 4a). Similarly, C21 infusion (5 μg kg−1 min−1) caused a significant increase in FELi (Basal: 24.6±2.9, C21: 56.8±5.5 %, P<0.05) (Figure 4b). The C21 infusion in AM + BFTZ-infused rats caused a further increase in both the UF and the UNaV. These findings suggest that the majority of C21-induced natriuresis originates from the proximal nephron segments; however, the findings do not rule out the possibility of involvement at the loop of Henle. Hypertens Res. 2012 Jun; 35(6): 654–660. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3912844/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 100.0 210.25

Preparing Stock Solutions

The following data is based on the product molecular weight 475.62 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Sampson AK, Irvine JC, Shihata WA, Dragoljevic D, Lumsden N, Huet O, Barnes T, Unger T, Steckelings UM, Jennings GL, Widdop RE, Chin-Dusting JP. Compound 21, a selective agonist of angiotensin AT2 receptors, prevents endothelial inflammation and leukocyte adhesion in vitro and in vivo. Br J Pharmacol. 2016 Feb;173(4):729-40. doi: 10.1111/bph.13063. Epub 2015 Jun 29. PMID: 25560767; PMCID: PMC4742292. 2. Fouda AY, Pillai B, Dhandapani KM, Ergul A, Fagan SC. Role of interleukin-10 in the neuroprotective effect of the Angiotensin Type 2 Receptor agonist, compound 21, after ischemia/reperfusion injury. Eur J Pharmacol. 2017 Mar 15;799:128-134. doi: 10.1016/j.ejphar.2017.02.016. Epub 2017 Feb 10. PMID: 28192099; PMCID: PMC5411859. 3. Ali Q, Hussain T. AT2 receptor non-peptide agonist C21 promotes natriuresis in obese Zucker rats. Hypertens Res. 2012 Jun;35(6):654-60. doi: 10.1038/hr.2012.13. Epub 2012 Feb 2. PMID: 22297475; PMCID: PMC3912844. 4. Ali Q, Patel S, Hussain T. Angiotensin AT2 receptor agonist prevents salt-sensitive hypertension in obese Zucker rats. Am J Physiol Renal Physiol. 2015 Jun 15;308(12):F1379-85. doi: 10.1152/ajprenal.00002.2015. Epub 2015 Apr 8. PMID: 25855512; PMCID: PMC4469886.
In vitro protocol: 1. Sampson AK, Irvine JC, Shihata WA, Dragoljevic D, Lumsden N, Huet O, Barnes T, Unger T, Steckelings UM, Jennings GL, Widdop RE, Chin-Dusting JP. Compound 21, a selective agonist of angiotensin AT2 receptors, prevents endothelial inflammation and leukocyte adhesion in vitro and in vivo. Br J Pharmacol. 2016 Feb;173(4):729-40. doi: 10.1111/bph.13063. Epub 2015 Jun 29. PMID: 25560767; PMCID: PMC4742292. 2. Fouda AY, Pillai B, Dhandapani KM, Ergul A, Fagan SC. Role of interleukin-10 in the neuroprotective effect of the Angiotensin Type 2 Receptor agonist, compound 21, after ischemia/reperfusion injury. Eur J Pharmacol. 2017 Mar 15;799:128-134. doi: 10.1016/j.ejphar.2017.02.016. Epub 2017 Feb 10. PMID: 28192099; PMCID: PMC5411859.
In vivo protocol: 1. Ali Q, Hussain T. AT2 receptor non-peptide agonist C21 promotes natriuresis in obese Zucker rats. Hypertens Res. 2012 Jun;35(6):654-60. doi: 10.1038/hr.2012.13. Epub 2012 Feb 2. PMID: 22297475; PMCID: PMC3912844. 2. Ali Q, Patel S, Hussain T. Angiotensin AT2 receptor agonist prevents salt-sensitive hypertension in obese Zucker rats. Am J Physiol Renal Physiol. 2015 Jun 15;308(12):F1379-85. doi: 10.1152/ajprenal.00002.2015. Epub 2015 Apr 8. PMID: 25855512; PMCID: PMC4469886.

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1: Isaksson R, Casselbrant A, Elebring E, Hallberg M, Larhed M, Fändriks L. Direct stimulation of angiotensin II type 2 receptor reduces nitric oxide production in lipopolysaccharide treated mouse macrophages. Eur J Pharmacol. 2020 Feb 5;868:172855. doi: 10.1016/j.ejphar.2019.172855. Epub 2019 Dec 16. PubMed PMID: 31837306.

2: Khorooshi R, Tofte-Hansen EU, Tygesen C, Montanana-Rosell R, Limburg HL, Marczynska J, Asgari N, Steckelings UM, Owens T. Angiotensin AT2 receptor-induced interleukin-10 attenuates neuromyelitis optica spectrum disorder-like pathology. Mult Scler. 2019 Jul 9:1352458519860327. doi: 10.1177/1352458519860327. [Epub ahead of print] PubMed PMID: 31287367.

3: Patel S, Dhande I, Gray EA, Ali Q, Hussain T. Prevention of lipopolysaccharide-induced CD11b(+) immune cell infiltration in the kidney: role of AT(2) receptors. Biosci Rep. 2019 May 23;39(5). pii: BSR20190429. doi: 10.1042/BSR20190429. Print 2019 May 31. PubMed PMID: 31072913; PubMed Central PMCID: PMC6533357.

4: Ahmed HA, Ishrat T, Pillai B, Bunting KM, Vazdarjanova A, Waller JL, Ergul A, Fagan SC. Angiotensin receptor (AT2R) agonist C21 prevents cognitive decline after permanent stroke in aged animals-A randomized double- blind pre-clinical study. Behav Brain Res. 2019 Feb 1;359:560-569. doi: 10.1016/j.bbr.2018.10.010. Epub 2018 Oct 5. PubMed PMID: 30296528; PubMed Central PMCID: PMC6371811.

5: Castoldi G, di Gioia CRT, Roma F, Carletti R, Manzoni G, Stella A, Zerbini G, Perseghin G. Activation of angiotensin type 2 (AT2) receptors prevents myocardial hypertrophy in Zucker diabetic fatty rats. Acta Diabetol. 2019 Jan;56(1):97-104. doi: 10.1007/s00592-018-1220-1. Epub 2018 Sep 5. PubMed PMID: 30187136.

6: Shan BS, Mogi M, Iwanami J, Bai HY, Kan-No H, Higaki A, Min LJ, Horiuchi M. Attenuation of stroke damage by angiotensin II type 2 receptor stimulation via peroxisome proliferator-activated receptor-gamma activation. Hypertens Res. 2018 Oct;41(10):839-848. doi: 10.1038/s41440-018-0082-9. Epub 2018 Aug 8. PubMed PMID: 30089862.

7: Lange C, Sommerfeld M, Namsolleck P, Kintscher U, Unger T, Kaschina E. AT(2)R (Angiotensin AT2 Receptor) Agonist, Compound 21, Prevents Abdominal Aortic Aneurysm Progression in the Rat. Hypertension. 2018 Sep;72(3):e20-e29. doi: 10.1161/HYPERTENSIONAHA.118.11168. PubMed PMID: 29987108.

8: Menk M, Graw JA, von Haefen C, Steinkraus H, Lachmann B, Spies CD, Schwaiberger D. Angiotensin II type 2 receptor agonist Compound 21 attenuates pulmonary inflammation in a model of acute lung injury. J Inflamm Res. 2018 May 1;11:169-178. doi: 10.2147/JIR.S160573. eCollection 2018. PubMed PMID: 29750051; PubMed Central PMCID: PMC5935084.

9: Rathinasabapathy A, Horowitz A, Horton K, Kumar A, Gladson S, Unger T, Martinez D, Bedse G, West J, Raizada MK, Steckelings UM, Sumners C, Katovich MJ, Shenoy V. The Selective Angiotensin II Type 2 Receptor Agonist, Compound 21, Attenuates the Progression of Lung Fibrosis and Pulmonary Hypertension in an Experimental Model of Bleomycin-Induced Lung Injury. Front Physiol. 2018 Mar 27;9:180. doi: 10.3389/fphys.2018.00180. eCollection 2018. PubMed PMID: 29636695; PubMed Central PMCID: PMC5881224.

10: Peluso AA, Bertelsen JB, Andersen K, Mortsensen TP, Hansen PB, Sumners C, Bader M, Santos RA, Steckelings UM. Identification of protein phosphatase involvement in the AT(2) receptor-induced activation of endothelial nitric oxide synthase. Clin Sci (Lond). 2018 Apr 6;132(7):777-790. doi: 10.1042/CS20171598. Print 2018 Apr 16. PubMed PMID: 29540539.

11: Bennion DM, Jones CH, Dang AN, Isenberg J, Graham JT, Lindblad L, Domenig O, Waters MF, Poglitsch M, Sumners C, Steckelings UM. Protective effects of the angiotensin II AT(2) receptor agonist compound 21 in ischemic stroke: a nose-to-brain delivery approach. Clin Sci (Lond). 2018 Mar 15;132(5):581-593. doi: 10.1042/CS20180100. Print 2018 Mar 15. PubMed PMID: 29500223.

12: Pandey A, Gaikwad AB. AT(2) receptor agonist Compound 21: A silver lining for diabetic nephropathy. Eur J Pharmacol. 2017 Nov 15;815:251-257. doi: 10.1016/j.ejphar.2017.09.036. Epub 2017 Sep 21. Review. PubMed PMID: 28943106.

13: Wang Y, Del Borgo M, Lee HW, Baraldi D, Hirmiz B, Gaspari TA, Denton KM, Aguilar MI, Samuel CS, Widdop RE. Anti-fibrotic Potential of AT(2) Receptor Agonists. Front Pharmacol. 2017 Aug 31;8:564. doi: 10.3389/fphar.2017.00564. eCollection 2017. Review. PubMed PMID: 28912715; PubMed Central PMCID: PMC5583590.

14: Hallberg M, Sumners C, Steckelings UM, Hallberg A. Small-molecule AT2 receptor agonists. Med Res Rev. 2018 Mar;38(2):602-624. doi: 10.1002/med.21449. Epub 2017 Jun 13. Review. PubMed PMID: 28609561.

15: Fouda AY, Pillai B, Dhandapani KM, Ergul A, Fagan SC. Role of interleukin-10 in the neuroprotective effect of the Angiotensin Type 2 Receptor agonist, compound 21, after ischemia/reperfusion injury. Eur J Pharmacol. 2017 Mar 15;799:128-134. doi: 10.1016/j.ejphar.2017.02.016. Epub 2017 Feb 10. PubMed PMID: 28192099; PubMed Central PMCID: PMC5411859.

16: Hallberg M, Sävmarker J, Hallberg A. Angiotensin Peptides as AT2 Receptor Agonists. Curr Protein Pept Sci. 2017;18(8):809-818. doi: 10.2174/1389203718666170203150344. Review. PubMed PMID: 28164758.

17: Bai HY, Mogi M, Nakaoka H, Kan-No H, Tsukuda K, Wang XL, Shan BS, Kukida M, Yamauchi T, Higaki A, Min LJ, Iwanami J, Horiuchi M. Synergistic Inhibitory Effect of Rosuvastatin and Angiotensin II Type 2 Receptor Agonist on Vascular Remodeling. J Pharmacol Exp Ther. 2016 Aug;358(2):352-8. doi: 10.1124/jpet.116.233148. Epub 2016 May 25. PubMed PMID: 27225894.

18: Chow BS, Koulis C, Krishnaswamy P, Steckelings UM, Unger T, Cooper ME, Jandeleit-Dahm KA, Allen TJ. The angiotensin II type 2 receptor agonist Compound 21 is protective in experimental diabetes-associated atherosclerosis. Diabetologia. 2016 Aug;59(8):1778-90. doi: 10.1007/s00125-016-3977-5. Epub 2016 May 11. PubMed PMID: 27168137.

19: Mateos L, Perez-Alvarez MJ, Wandosell F. Angiotensin II type-2 receptor stimulation induces neuronal VEGF synthesis after cerebral ischemia. Biochim Biophys Acta. 2016 Jul;1862(7):1297-308. doi: 10.1016/j.bbadis.2016.03.013. Epub 2016 Apr 1. PubMed PMID: 27045356.

20: Patel SN, Ali Q, Hussain T. Angiotensin II Type 2-Receptor Agonist C21 Reduces Proteinuria and Oxidative Stress in Kidney of High-Salt-Fed Obese Zucker Rats. Hypertension. 2016 May;67(5):906-15. doi: 10.1161/HYPERTENSIONAHA.115.06881. Epub 2016 Mar 28. PubMed PMID: 27021008; PubMed Central PMCID: PMC4833537.