brensocatib   Click here for help

GtoPdb Ligand ID: 9412

Synonyms: AZD7986 | compound 30 [1] | INS 1007 | INS1007
Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: Brensocatib (formerly AZD7986) is reported as a second generation, oral, selective and reversible inhibitor of dipeptidyl peptidase 1 (DPP1; a.k.a. cathepsin C) [1]. Cathepsin C is required for the activation of proinflammatory neutrophil serine proteases, making this enzyme a drug target whose pharmacological inhibition has potential in the treatment of diseases such as chronic obstructive pulmonary disease (COPD) which is driven in part by excessive neutrophil activation and dysregulated neutrophil elastase activity. The compound was originally developed by AstraZeneca, but is now being progressed by Insmed.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 6
Hydrogen bond donors 2
Rotatable bonds 6
Topological polar surface area 109.29
Molecular weight 420.18
XLogP 2
No. Lipinski's rules broken 0
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Canonical SMILES N#CC(Cc1ccc(cc1)c1ccc2c(c1)n(C)c(=O)o2)NC(=O)C1CNCCCO1
Isomeric SMILES N#C[C@H](Cc1ccc(cc1)c1ccc2c(c1)n(C)c(=O)o2)NC(=O)[C@@H]1CNCCCO1
InChI 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
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Summary of Clinical Use Click here for help
Brensocatib (formerly AZD7986) has completed Phase 1 clinical trials in healthy volunteers (see NCT02303574 and NCT02653872) which confirm on-target effects [2]. Insmed are progressing AZD7986 (re-assigned as INS1007) as an anti-inflammatory approach to treat the cycle of inflammation, infection, and debilitating lung damage that is associated with non-cystic fibrosis bronchiectasis (NCFBE).

SARS-CoV-2 and COVID-19: Plans are underway to examine the potential of INS1007 to treat COVID-19-related acute respiratory distress syndrome (ARDS), in the UK STOP-COVID19 clinical trial which is being led from the University of Dundee. The INS1007 arm of the study aims to administer the drug to 150 COVID-19 patients (plus 150 in the placebo arm) across 10 UK hospitals.
Mechanism Of Action and Pharmacodynamic Effects Click here for help
Cathepsin C cleaves the N-terminal dipeptide of neutrophil serine proteases (NSPs) during neutrophil maturation in the bone marrow. This action leads to neutrophils without stored activated NSPs (e.g. neutrophil elastase, proteinase 3, and cathepsin G). In neutrophil-driven lung disease, treatment with cathepsin C inhibitors should reduce availability of the active NSPs that cause inflammatory lung damage, leading to improvement of disease symptoms.
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT02653872 A Phase I Study to Assess PK of AZD7986 Alone & With Verapamil, Itraconazole or Diltiazem in Healthy Subjects Phase 1 Interventional AstraZeneca
NCT02303574 Single + Multiple Ascending Dose and Food Effect Study of AZD7986 in Healthy Volunteers, PK, PD and Safety Study Phase 1 Interventional AstraZeneca
NCT03218917 Assessment of INS1007 in Subjects With Non-Cystic Fibrosis Bronchiectasis Phase 2 Interventional Insmed Incorporated This trial has been completed, but as of April 2020 no results have been published. The Insmed website indicates that they are planning to progress INS1007 to Phase 3 in bronchiectasis following positive top-line results from this study.