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MedKoo Cat#: 206473 | Name: AZD-5069
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

AZD-5069 is a potent and selective CXCR2 antagonist with the potential to inhibit neutrophil migration into the airways in patients with COPD. AZD-5069 was shown to inhibit binding of radiolabeled CXCL8 to human CXCR2 with a pIC50 value of 9.1. Furthermore, AZD5069 inhibited neutrophil chemotaxis, with a pA2 of approximately 9.6, and adhesion molecule expression, with a pA2 of 6.9, in response to CXCL1. AZD5069 was a slowly reversible antagonist of CXCR2 with effects of time and temperature evident on the pharmacology and binding kinetics. AZD-5069 is also potential useful for patient in inflammatory conditions.

Chemical Structure

AZD-5069
AZD-5069
CAS#878385-84-3

Theoretical Analysis

MedKoo Cat#: 206473

Name: AZD-5069

CAS#: 878385-84-3

Chemical Formula: C18H22F2N4O5S2

Exact Mass: 476.1000

Molecular Weight: 476.51

Elemental Analysis: C, 45.37; H, 4.65; F, 7.97; N, 11.76; O, 16.79; S, 13.46

Price and Availability

Size Price Availability Quantity
5mg USD 90.00 Ready to ship
10mg USD 150.00 Ready to ship
25mg USD 250.00 Ready to ship
50mg USD 450.00 Ready to ship
100mg USD 750.00 Ready to ship
200mg USD 1,250.00 Ready to ship
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Related CAS #
No Data
Synonym
AZD-5069; AZD 5069; AZD5069.
IUPAC/Chemical Name
N-(2-((2,3-difluorobenzyl)thio)-6-(((2R,3S)-3,4-dihydroxybutan-2-yl)oxy)pyrimidin-4-yl)azetidine-1-sulfonamide
InChi Key
QZECRCLSIGFCIO-RISCZKNCSA-N
InChi Code
InChI=1S/C18H22F2N4O5S2/c1-11(14(26)9-25)29-16-8-15(23-31(27,28)24-6-3-7-24)21-18(22-16)30-10-12-4-2-5-13(19)17(12)20/h2,4-5,8,11,14,25-26H,3,6-7,9-10H2,1H3,(H,21,22,23)/t11-,14+/m1/s1
SMILES Code
O=S(N1CCC1)(NC2=NC(SCC3=CC=CC(F)=C3F)=NC(O[C@H](C)[C@@H](O)CO)=C2)=O
Appearance
White to off-white 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, not in water
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:
AZD 5069 is an antagonist of chemokine receptor 2 (CXCR2; IC50 = 0.79 nM in a radioligand binding assay). It inhibits CXCL1-induced CD11b expression in and chemotaxis of isolated human neutrophils (pA2s = 6.9 and 9.1, respectively). AZD 5069 (3 and 10 μmol/kg) inhibits bronchoalveolar lavage fluid (BALF) neutrophil influx in a rat model of LPS-induced lung neutrophilia and non-allergic airway inflammation.
In vitro activity:
AZD5069 (3 nM) produced a concentration-dependent inhibition of calcium flux induced by CXCL8 (Fig. 5B). The inhibition of functional responses to CXCL8 by AZD5069 was reversible after compound was removed by washing cells. Although the washing procedure used to remove compound from the system was able to demonstrate that inhibition by AZD5069 was reversible, complete restoration of the CXCL8-mediated calcium response to control levels was not observed. AZD5069 produced a concentration-dependent inhibition of PMN chemotaxis induced by CXCL1 (Fig. 6A). Agonist response curves appeared to collapse in the presence of AZD5069. Although response to a gradient of chemokine is not a simple equilibrium-driven system, the pA2 for AZD5069 was estimated to be approximately 9.6 (range 9.2–9.9). The integrin CD11b is upregulated on neutrophils in response to a variety of inflammatory mediators. AZD5069 produced clear inhibition of CXCL1-mediated CD11b expression with a rightward shift of the concentration effect curve to CXCL1 (Fig. 6B), with a pA2 of 6.9 6 0.13 (mean 6 S.E.M., n 5 8). CXCL1 agonist response curves also appeared to collapse in the presence of AZD5069 (Fig. 6B). When several agonists inducing CD11b expression on neutrophils were investigated, a high concentration of AZD5069 was found to specifically inhibit only the CXCL1-driven response with no significant inhibition observed for neutrophils stimulated by C5a, N-formyl-methionyl-leucylphenylalanine, or leukotriene B4 (Fig. 7). Reference: J Pharmacol Exp Ther. 2015 May;353(2):340-50. https://jpet-aspetjournals-org.libproxy.lib.unc.edu/content/jpet/353/2/340.full.pdf
In vivo activity:
Analysis of the general toxicological data from 39 weeks of treatment revealed that dosing regimens of up to 525 mg/kg/day were well tolerated in cynomolgus monkeys. AZD5069 had no significant impact on most of the measured parameters. However, an increase in circulating globulin and a decrease in albumin (with a consequent reduction in the albumin/globulin ratio) was seen in a reciprocal manner, that was not dose-related. Furthermore, AZD5069-related histopathological findings were limited to the bone marrow consisting of a dose-related increment in the myeloid/erythroid ratio, with an associated increase in segmented granulocytes at all dose levels. Notably, no compound-related changes in baseline circulating neutrophil numbers were evident (data not shown), despite an apparently similar expression pattern of CXCR2 receptors to humans,10 which indicated that AZD5069 did not affect the neutrophil mobilization from the bone marrow into the peripheral circulation under homeostatic conditions. The sparing effect of AZD5069 treatment on circulating neutrophils is particularly noteworthy in this context, since there was no increased risk of infection in animals chronically treated with AZD5069 over the 39 week interval in vivo, which is reflective of the preserved pathogen-initiated phagocytic and oxidative responses observed in the high percentage of neutrophils responding normally ex vivo. Reference: Haematologica. 2017 Feb; 102(2): e65–e68. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5286957/
Solvent mg/mL mM
Solubility
DMSO 90.0 188.87
Ethanol 7.0 14.69
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 476.51 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. Nicholls DJ, Wiley K, Dainty I, MacIntosh F, Phillips C, Gaw A, Mårdh CK. Pharmacological characterization of AZD5069, a slowly reversible CXC chemokine receptor 2 antagonist. J Pharmacol Exp Ther. 2015 May;353(2):340-50. doi: 10.1124/jpet.114.221358. Epub 2015 Mar 3. PMID: 25736418. 2. Armstrong CWD, Coulter JA, Ong CW, Maxwell PJ, Walker S, Butterworth KT, Lyubomska O, Berlingeri S, Gallagher R, O'Sullivan JM, Jain S, Mills IG, Prise KM, Bristow RG, LaBonte MJ, Waugh DJJ. Clinical and functional characterization of CXCR1/CXCR2 biology in the relapse and radiotherapy resistance of primary PTEN-deficient prostate carcinoma. NAR Cancer. 2020 Sep;2(3):zcaa012. doi: 10.1093/narcan/zcaa012. Epub 2020 Jul 3. PMID: 32743555; PMCID: PMC7380483. 3. Uddin M, Betts C, Robinson I, Malmgren A, Humfrey C. The chemokine CXCR2 antagonist (AZD5069) preserves neutrophil-mediated host immunity in non-human primates. Haematologica. 2017 Feb;102(2):e65-e68. doi: 10.3324/haematol.2016.152371. Epub 2016 Oct 14. PMID: 27742769; PMCID: PMC5286957. 4. Sody S, Uddin M, Grüneboom A, Görgens A, Giebel B, Gunzer M, Brandau S. Distinct Spatio-Temporal Dynamics of Tumor-Associated Neutrophils in Small Tumor Lesions. Front Immunol. 2019 Jun 25;10:1419. doi: 10.3389/fimmu.2019.01419. PMID: 31293583; PMCID: PMC6603174.
In vitro protocol:
1. Nicholls DJ, Wiley K, Dainty I, MacIntosh F, Phillips C, Gaw A, Mårdh CK. Pharmacological characterization of AZD5069, a slowly reversible CXC chemokine receptor 2 antagonist. J Pharmacol Exp Ther. 2015 May;353(2):340-50. doi: 10.1124/jpet.114.221358. Epub 2015 Mar 3. PMID: 25736418. 2. Armstrong CWD, Coulter JA, Ong CW, Maxwell PJ, Walker S, Butterworth KT, Lyubomska O, Berlingeri S, Gallagher R, O'Sullivan JM, Jain S, Mills IG, Prise KM, Bristow RG, LaBonte MJ, Waugh DJJ. Clinical and functional characterization of CXCR1/CXCR2 biology in the relapse and radiotherapy resistance of primary PTEN-deficient prostate carcinoma. NAR Cancer. 2020 Sep;2(3):zcaa012. doi: 10.1093/narcan/zcaa012. Epub 2020 Jul 3. PMID: 32743555; PMCID: PMC7380483.
In vivo protocol:
1. Uddin M, Betts C, Robinson I, Malmgren A, Humfrey C. The chemokine CXCR2 antagonist (AZD5069) preserves neutrophil-mediated host immunity in non-human primates. Haematologica. 2017 Feb;102(2):e65-e68. doi: 10.3324/haematol.2016.152371. Epub 2016 Oct 14. PMID: 27742769; PMCID: PMC5286957. 2. Sody S, Uddin M, Grüneboom A, Görgens A, Giebel B, Gunzer M, Brandau S. Distinct Spatio-Temporal Dynamics of Tumor-Associated Neutrophils in Small Tumor Lesions. Front Immunol. 2019 Jun 25;10:1419. doi: 10.3389/fimmu.2019.01419. PMID: 31293583; PMCID: PMC6603174.
1: Uddin M, Watz H, Malmgren A, Pedersen F. NETopathic Inflammation in Chronic Obstructive Pulmonary Disease and Severe Asthma. Front Immunol. 2019 Feb 5;10:47. doi: 10.3389/fimmu.2019.00047. PMID: 30804927; PMCID: PMC6370641. 2: Cullberg M, Arfvidsson C, Larsson B, Malmgren A, Mitchell P, Wählby Hamrén U, Wray H. Pharmacokinetics of the Oral Selective CXCR2 Antagonist AZD5069: A Summary of Eight Phase I Studies in Healthy Volunteers. Drugs R D. 2018 Jun;18(2):149-159. doi: 10.1007/s40268-018-0236-x. PMID: 29856004; PMCID: PMC5995788. 3: De Soyza A, Pavord I, Elborn JS, Smith D, Wray H, Puu M, Larsson B, Stockley R. A randomised, placebo-controlled study of the CXCR2 antagonist AZD5069 in bronchiectasis. Eur Respir J. 2015 Oct;46(4):1021-32. doi: 10.1183/13993003.00148-2015. Epub 2015 Sep 4. PMID: 26341987. 4: Hickey MJ, Allen PH, Caffrey M, Hansen P, Kingston LP, Wilkinson DJ. Syntheses of a radiolabelled CXCR2 antagonist AZD5069 and its major human metabolite. J Labelled Comp Radiopharm. 2016 Sep;59(11):432-8. doi: 10.1002/jlcr.3429. Epub 2016 Jul 27. PMID: 27461061. 5: Watz H, Uddin M, Pedersen F, Kirsten A, Goldmann T, Stellmacher F, Groth E, Larsson B, Böttcher G, Malmgren A, Kraan M, Rabe KF. Effects of the CXCR2 antagonist AZD5069 on lung neutrophil recruitment in asthma. Pulm Pharmacol Ther. 2017 Aug;45:121-123. doi: 10.1016/j.pupt.2017.05.012. Epub 2017 May 23. PMID: 28549850. 6: Nicholls DJ, Wiley K, Dainty I, MacIntosh F, Phillips C, Gaw A, Mårdh CK. Pharmacological characterization of AZD5069, a slowly reversible CXC chemokine receptor 2 antagonist. J Pharmacol Exp Ther. 2015 May;353(2):340-50. doi: 10.1124/jpet.114.221358. Epub 2015 Mar 3. PMID: 25736418. 7: Kirsten AM, Förster K, Radeczky E, Linnhoff A, Balint B, Watz H, Wray H, Salkeld L, Cullberg M, Larsson B. The safety and tolerability of oral AZD5069, a selective CXCR2 antagonist, in patients with moderate-to-severe COPD. Pulm Pharmacol Ther. 2015 Apr;31:36-41. doi: 10.1016/j.pupt.2015.02.001. Epub 2015 Feb 11. PMID: 25681277. 8: Di Mitri D, Mirenda M, Vasilevska J, Calcinotto A, Delaleu N, Revandkar A, Gil V, Boysen G, Losa M, Mosole S, Pasquini E, D'Antuono R, Masetti M, Zagato E, Chiorino G, Ostano P, Rinaldi A, Gnetti L, Graupera M, Martins Figueiredo Fonseca AR, Pereira Mestre R, Waugh D, Barry S, De Bono J, Alimonti A. Re- education of Tumor-Associated Macrophages by CXCR2 Blockade Drives Senescence and Tumor Inhibition in Advanced Prostate Cancer. Cell Rep. 2019 Aug 20;28(8):2156-2168.e5. doi: 10.1016/j.celrep.2019.07.068. PMID: 31433989; PMCID: PMC6715643. 9: O'Byrne PM, Metev H, Puu M, Richter K, Keen C, Uddin M, Larsson B, Cullberg M, Nair P. Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2016 Oct;4(10):797-806. doi: 10.1016/S2213-2600(16)30227-2. Epub 2016 Aug 27. PMID: 27574788. 10: Jurcevic S, Humfrey C, Uddin M, Warrington S, Larsson B, Keen C. The effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions. Br J Clin Pharmacol. 2015 Dec;80(6):1324-36. doi: 10.1111/bcp.12724. Epub 2015 Oct 2. PMID: 26182832; PMCID: PMC4693488. 11: Uddin M, Betts C, Robinson I, Malmgren A, Humfrey C. The chemokine CXCR2 antagonist (AZD5069) preserves neutrophil-mediated host immunity in non-human primates. Haematologica. 2017 Feb;102(2):e65-e68. doi: 10.3324/haematol.2016.152371. Epub 2016 Oct 14. PMID: 27742769; PMCID: PMC5286957. 12: Sody S, Uddin M, Grüneboom A, Görgens A, Giebel B, Gunzer M, Brandau S. Distinct Spatio-Temporal Dynamics of Tumor-Associated Neutrophils in Small Tumor Lesions. Front Immunol. 2019 Jun 25;10:1419. doi: 10.3389/fimmu.2019.01419. PMID: 31293583; PMCID: PMC6603174. 13: Gardiner P, Cox RJ, Grime K. Plasma Protein Binding as an Optimizable Parameter for Acidic Drugs. Drug Metab Dispos. 2019 Aug;47(8):865-873. doi: 10.1124/dmd.119.087163. Epub 2019 May 21. PMID: 31113795. 14: Joseph JP, Reyes E, Guzman J, O'Doherty J, McConkey H, Arri S, Kakkar R, Beckley N, Douiri A, Barrington SF, Redwood SR, Ferro A. CXCR2 Inhibition - a novel approach to treating CoronAry heart DiseAse (CICADA): study protocol for a randomised controlled trial. Trials. 2017 Oct 11;18(1):473. doi: 10.1186/s13063-017-2210-2. PMID: 29020983; PMCID: PMC5637263. 15: Yousuf A, Brightling CE. Biologic Drugs: A New Target Therapy in COPD? COPD. 2018 Apr;15(2):99-107. doi: 10.1080/15412555.2018.1437897. Epub 2018 Apr 23. PMID: 29683730. 16: Armstrong CWD, Coulter JA, Ong CW, Maxwell PJ, Walker S, Butterworth KT, Lyubomska O, Berlingeri S, Gallagher R, O'Sullivan JM, Jain S, Mills IG, Prise KM, Bristow RG, LaBonte MJ, Waugh DJJ. Clinical and functional characterization of CXCR1/CXCR2 biology in the relapse and radiotherapy resistance of primary PTEN-deficient prostate carcinoma. NAR Cancer. 2020 Sep;2(3):zcaa012. doi: 10.1093/narcan/zcaa012. Epub 2020 Jul 3. PMID: 32743555; PMCID: PMC7380483. 17: Gross N. The COPD Pipeline XXX. Chronic Obstr Pulm Dis. 2015 Dec 14;3(1):498-502. doi: 10.15326/jcopdf.3.1.2015.0181. PMID: 28848873; PMCID: PMC5559133. 18: Martínez-García MÁ, Sánchez CP, Moreno RM. The double-edged sword of neutrophilic inflammation in bronchiectasis. Eur Respir J. 2015 Oct;46(4):898-900. doi: 10.1183/13993003.00961-2015. PMID: 26424521. 19: Pedersen F, Waschki B, Marwitz S, Goldmann T, Kirsten A, Malmgren A, Rabe KF, Uddin M, Watz H. Neutrophil extracellular trap formation is regulated by CXCR2 in COPD neutrophils. Eur Respir J. 2018 Apr 12;51(4):1700970. doi: 10.1183/13993003.00970-2017. PMID: 29449427. 20: Norman P. Evidence on the identity of the CXCR2 antagonist AZD-5069. Expert Opin Ther Pat. 2013 Jan;23(1):113-7. doi: 10.1517/13543776.2012.725724. Epub 2012 Sep 20. PMID: 22992174.

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