AZD7986
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MedKoo CAT#: 526881

CAS#: 1802148-05-5

Description: Brensocatib, also known as AZD7986, INS 1007, is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases. AZD 7986 inhibits activation of the DPP-1 targets neutrophil elastase, proteinase 3, and cathepsin G in human bone marrow-derived CD34+ neutrophil progenitor cells (IC50s = 61.7, 208.9, and 114.8 nM, respectively). AZD7986 inhibits whole blood NE activity in an exposure-dependent, indirect manner-consistent with in vitro and preclinical predictions.

Chemical Structure

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AZD7986
CAS# 1802148-05-5
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 526881
Name: AZD7986
CAS#: 1802148-05-5
Chemical Formula: C23H24N4O4
Exact Mass: 420.18
Molecular Weight: 420.469
Elemental Analysis: C, 65.70; H, 5.75; N, 13.33; O, 15.22

Price and Availability

Size Price Availability Quantity
5mg USD 150 Ready to ship
10mg USD 250 Ready to ship
25mg USD 550 Ready to ship
50mg USD 900 Ready to ship
100mg USD 1450 Ready to ship
200mg USD 2250 Ready to ship
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Synonym: AZD7986; AZD-7986; AZD 7986; INS 1007; INS-1007; INS1007, Brensocatib

IUPAC/Chemical Name: (S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide

InChi Key: AEXFXNFMSAAELR-RXVVDRJESA-N

InChi Code: InChI=1S/C23H24N4O4/c1-27-19-12-17(7-8-20(19)31-23(27)29)16-5-3-15(4-6-16)11-18(13-24)26-22(28)21-14-25-9-2-10-30-21/h3-8,12,18,21,25H,2,9-11,14H2,1H3,(H,26,28)/t18-,21-/m0/s1

SMILES Code: N#C[C@H](CC1=CC=C(C2=CC=C(OC(N3C)=O)C3=C2)C=C1)NC([C@H]4OCCCNC4)=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: Brensocatib reduces exacerbations of bronchiectasis by approximately 40 percent as learned in a phase 2 trial. Bronchiectasis is chronic inflammation and dilation of the airways that results from damage caused by respiratory infections, genetic diseases such as cystic fibrosis, alpha-1 antitrypsin deficiency, and other insults to the airways. The damaged airways lose the ability to clear mucus and bacteria, leading to repeated infections that further damage the airways. The only existing medications to reduce exacerbations are inhaled antibiotics, which are time consuming to administer and eventually lead to resistant organisms.

Biological target: Brensocatib (AZD7986) is a dipeptidyl peptidase 1 (DPP1) inhibitor with pIC50s of 6.85, 7.6, 7.7, 7.8, and 7.8 in human, mouse, rat, dog and rabbit, respectively
In vitro activity: The effect of DPP1 inhibition from AZD7986 (compound 30) on the activation of NSPs was studied in vitro using human primary bone marrow-derived CD34+ neutrophil progenitor cells. After differentiation in the presence of compound 30 (38 pM to 10 μM), concentration-dependent decreases in cell lysate enzyme activity were observed for DPP1, as well as for all of the three NSPs, NE, Pr3, and CatG (Figure 5). In conclusion compound 30 inhibited activation of all three NSPs in a concentration dependent manner, with pIC50 values of around 7 for all three NSPs (Figure 5 and Table 7). The reduction of the activities was almost complete, with NE, Pr3, and CatG activities reduced to 4–10% of control at 10 μM 30 (Figure 5). Reference: J Med Chem. 2016 Oct 27;59(20):9457-9472. https://doi.org/10.1021/acs.jmedchem.6b01127
In vivo activity: The ability of compound 30 to inhibit activation of NSPs in vivo was assessed by treatment of naive rats with the compound twice daily (0.2, 2, and 20 mg kg–1 day–1) for 8 days. Compound 30 inhibited activation of NE and Pr3, but not CatG, in bone marrow cell lysates in a dose dependent manner in vivo (Figure 6). Variability in the CatG assay was due to the colormetric substrate used, as opposed to fluorometric substrates used in the NE and Pr3 assays. Reference: J Med Chem. 2016 Oct 27;59(20):9457-9472. https://doi.org/10.1021/acs.jmedchem.6b01127

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 100.0 237.83

Preparing Stock Solutions

The following data is based on the product molecular weight 420.47 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:
In vitro protocol: 1. Doyle K, Lönn H, Käck H, Van de Poël A, Swallow S, Gardiner P, Connolly S, Root J, Wikell C, Dahl G, Stenvall K, Johannesson P. Discovery of Second Generation Reversible Covalent DPP1 Inhibitors Leading to an Oxazepane Amidoacetonitrile Based Clinical Candidate (AZD7986). J Med Chem. 2016 Oct 27;59(20):9457-9472. doi: 10.1021/acs.jmedchem.6b01127. Epub 2016 Oct 11. PMID: 27690432.
In vivo protocol: 1. Doyle K, Lönn H, Käck H, Van de Poël A, Swallow S, Gardiner P, Connolly S, Root J, Wikell C, Dahl G, Stenvall K, Johannesson P. Discovery of Second Generation Reversible Covalent DPP1 Inhibitors Leading to an Oxazepane Amidoacetonitrile Based Clinical Candidate (AZD7986). J Med Chem. 2016 Oct 27;59(20):9457-9472. doi: 10.1021/acs.jmedchem.6b01127. Epub 2016 Oct 11. PMID: 27690432.

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1: Sun L, Han X, Egeblad M. Isolation of mouse mammary carcinoma-derived macrophages and cancer cells for co-culture assays. STAR Protoc. 2022 Nov 10;3(4):101833. doi: 10.1016/j.xpro.2022.101833. PMID: 36386879; PMCID: PMC9664409.


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3: Chalmers JD, Usansky H, Rubino CM, Teper A, Fernandez C, Zou J, Mange KC. Pharmacokinetic/Pharmacodynamic Evaluation of the Dipeptidyl Peptidase 1 Inhibitor Brensocatib for Non-cystic Fibrosis Bronchiectasis. Clin Pharmacokinet. 2022 Oct;61(10):1457-1469. doi: 10.1007/s40262-022-01147-w. Epub 2022 Jul 25. PMID: 35976570; PMCID: PMC9553789.


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7: Usansky H, Yoon E, Teper A, Zou J, Fernandez C. Safety, Tolerability, and Pharmacokinetic Evaluation of Single and Multiple Doses of the Dipeptidyl Peptidase 1 Inhibitor Brensocatib in Healthy Japanese and White Adults. Clin Pharmacol Drug Dev. 2022 Jul;11(7):832-842. doi: 10.1002/cpdd.1094. Epub 2022 Apr 11. PMID: 35411669; PMCID: PMC9322451.


8: Adrover JM, Carrau L, Daßler-Plenker J, Bram Y, Chandar V, Houghton S, Redmond D, Merrill JR, Shevik M, tenOever BR, Lyons SK, Schwartz RE, Egeblad M. Disulfiram inhibits neutrophil extracellular trap formation and protects rodents from acute lung injury and SARS-CoV-2 infection. JCI Insight. 2022 Mar 8;7(5):e157342. doi: 10.1172/jci.insight.157342. PMID: 35133984; PMCID: PMC8983145.


9: Maiorino L, Shevik M, Adrover JM, Han X, Georgas E, Wilkinson JE, Seidner H, Foerschner L, Tuveson DA, Qin YX, Egeblad M. Longitudinal Intravital Imaging Through Clear Silicone Windows. J Vis Exp. 2022 Jan 5;(179):10.3791/62757. doi: 10.3791/62757. PMID: 35068483; PMCID: PMC9286001.


10: Korkmaz B, Lamort AS, Domain R, Beauvillain C, Gieldon A, Yildirim AÖ, Stathopoulos GT, Rhimi M, Jenne DE, Kettritz R. Cathepsin C inhibition as a potential treatment strategy in cancer. Biochem Pharmacol. 2021 Dec;194:114803. doi: 10.1016/j.bcp.2021.114803. Epub 2021 Oct 20. PMID: 34678221.


11: Shen XB, Chen X, Zhang ZY, Wu FF, Liu XH. Cathepsin C inhibitors as anti- inflammatory drug discovery: Challenges and opportunities. Eur J Med Chem. 2021 Dec 5;225:113818. doi: 10.1016/j.ejmech.2021.113818. Epub 2021 Sep 3. PMID: 34492551.


12: Sun L, Kees T, Almeida AS, Liu B, He XY, Ng D, Han X, Spector DL, McNeish IA, Gimotty P, Adams S, Egeblad M. Activating a collaborative innate-adaptive immune response to control metastasis. Cancer Cell. 2021 Oct 11;39(10):1361-1374.e9. doi: 10.1016/j.ccell.2021.08.005. Epub 2021 Sep 2. PMID: 34478639; PMCID: PMC8981964.


13: Fujii T, Rehman H, Chung SY, Shen J, Newman J, Wu V, Hines A, Azimi-Nekoo E, Fayyaz F, Lee M, Raptis G, Egeblad M, Zhu X. Treatment with Granulocyte-colony Stimulating Factor (G-CSF) is not associated with Increased Risk of Brain Metastasis in Patients with De Novo Stage IV Breast Cancer. J Cancer. 2021 Jul 25;12(18):5687-5692. doi: 10.7150/jca.63159. PMID: 34405029; PMCID: PMC8364654.


14: Xiao Y, Cong M, Li J, He D, Wu Q, Tian P, Wang Y, Yang S, Liang C, Liang Y, Wen J, Liu Y, Luo W, Lv X, He Y, Cheng DD, Zhou T, Zhao W, Zhang P, Zhang X, Xiao Y, Qian Y, Wang H, Gao Q, Yang QC, Yang Q, Hu G. Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophil extracellular trap formation. Cancer Cell. 2021 Mar 8;39(3):423-437.e7. doi: 10.1016/j.ccell.2020.12.012. Epub 2021 Jan 14. PMID: 33450198.


15: Kingston L, Gu C, Guo J, Swallow S, Elmore CS. The impact of radiochemistry in drug projects: The use of C-14 label in the AZD8529, AZD7325, and AZD6280 projects. J Labelled Comp Radiopharm. 2021 Feb;64(2):65-72. doi: 10.1002/jlcr.3902. Epub 2021 Jan 7. PMID: 33326121.


16: Chalmers JD, Haworth CS, Metersky ML, Loebinger MR, Blasi F, Sibila O, O'Donnell AE, Sullivan EJ, Mange KC, Fernandez C, Zou J, Daley CL; WILLOW Investigators. Phase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis. N Engl J Med. 2020 Nov 26;383(22):2127-2137. doi: 10.1056/NEJMoa2021713. Epub 2020 Sep 7. PMID: 32897034.


17: Ludvigsson JW, Wikström H, Andersson T, Norrby PO. Degradation caused by incompatibility between sodium stearyl fumarate (PRUV) and AZD7986 in the drug product. J Pharm Biomed Anal. 2018 Sep 5;158:82-87. doi: 10.1016/j.jpba.2018.05.036. Epub 2018 May 22. PMID: 29860182.


18: Palmér R, Mäenpää J, Jauhiainen A, Larsson B, Mo J, Russell M, Root J, Prothon S, Chialda L, Forte P, Egelrud T, Stenvall K, Gardiner P. Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure-Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects. Clin Pharmacol Ther. 2018 Dec;104(6):1155-1164. doi: 10.1002/cpt.1053. Epub 2018 Apr 16. PMID: 29484635; PMCID: PMC6282495.


19: Doyle K, Lönn H, Käck H, Van de Poël A, Swallow S, Gardiner P, Connolly S, Root J, Wikell C, Dahl G, Stenvall K, Johannesson P. Discovery of Second Generation Reversible Covalent DPP1 Inhibitors Leading to an Oxazepane Amidoacetonitrile Based Clinical Candidate (AZD7986). J Med Chem. 2016 Oct 27;59(20):9457-9472. doi: 10.1021/acs.jmedchem.6b01127. Epub 2016 Oct 11. PMID: 27690432.