Brensocatib (AZD7986), a dipeptidyl peptidase 1 (DPP1) inhibitor, has pIC50 values of 6.85, 7.6, 7.7, 7.8, and 7.8 in humans, mice, rats, dogs, and rabbits, respectively, according to the results of cell experiments. In propionaldehyde reactivity tests, brensocatib exhibits stability with a half-life of more than 50 hours. Following differentiation in the presence of 38 pM to 10 μM of Brensocatib, a concentration-dependent reduction in DPP1's and all three nsps' cytolytic enzyme activity—NE, Pr3, and CatG—was noted. With pIC50 values of roughly 7, brensocatib suppresses the activation of all three NSPs in a concentration-dependent manner. The level of activity has nearly entirely decreased. The activity of NE, Pr3, and CatG decrease to 4% to 10% of the control at 10 μM Brensocatib [1].

Brensocatib (AZD7986), a dipeptidyl peptidase 1 (DPP1) inhibitor, has pIC50 values of 6.85, 7.6, 7.7, 7.8, and 7.8 in humans, mice, rats, dogs, and rabbits, respectively, according to the results of cell experiments. In propionaldehyde reactivity tests, brensocatib exhibits stability with a half-life of more than 50 hours. Following differentiation in the presence of 38 pM to 10 μM of Brensocatib, a concentration-dependent reduction in DPP1's and all three nsps' cytolytic enzyme activity—NE, Pr3, and CatG—was noted. With pIC50 values of roughly 7, brensocatib suppresses the activation of all three NSPs in a concentration-dependent manner. The level of activity has nearly entirely decreased. The activity of NE, Pr3, and CatG decrease to 4% to 10% of the control at 10 μM Brensocatib [1].

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Brensocatib is a potent and reversible inhibitor of DPP1 enzyme and cellular activity. [1]
It inhibited the activation of neutrophil serine proteases (NE, Pr3, CatG) in differentiating human primary bone marrow-derived CD34+ neutrophil progenitor cells in a concentration-dependent manner, with pIC50 values around 7 for all three NSPs, reducing their activities to 4-10% of control at 10 µM. [1]
The compound showed high selectivity in a panel of >200 in vitro radioligand binding and enzyme assays. [1]

Brensocatib (AZD7986) has a half-life of more than 10 hours and shows good stability in plasma. In vivo, brensocatib dose-dependently suppresses the activation of NE and Pr3, but not CatG, in lysates of bone marrow cells [1].

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Administration of Brensocatib to naïve rats twice daily (0.2, 2, and 20 mg/kg/day) for eight days inhibited the activation of NE and Pr3, but not CatG, in bone marrow cell lysates in a dose-dependent manner. [1]

Inhibition of isolated human recombinant DPP1 enzyme activity was assessed using a fluorometric 384-well plate-based assay. Compounds were pre-incubated with the enzyme for 30 minutes at room temperature prior to addition of the fluorescent dipeptide substrate Gly-Arg-AMC. Potency values were obtained by fitting the data. [1]
Binding kinetics were characterized using a Surface Plasmon Resonance direct binding assay (SPR DBA). The interaction was described with a 1:1 model, resulting in an on-rate (kon) of 1.5E+6 (1/Ms), an off-rate (koff) of 4.0E-3 (1/s), a pKd of 8.6, and a residence time (half-life) of 3 minutes, confirming it is a reversible inhibitor. [1]

Cellular potency was studied using the DPP1-expressing monocytic U937 cell line. Cells were plated on 384-well plates, incubated with the DPP1 inhibitor at 37°C for 60 minutes, followed by addition of the substrate Gly-Phe-AFC. Fluorescence was read using a plate reader, and pIC50 values were calculated. [1]
The effect on NSP activation was assessed using primary human bone marrow-derived CD34+ neutrophil progenitor cells. Cells were cultured for seven days in growth media, then for a further seven days with G-CSF and different concentrations of compound 30. After harvesting and lysis, cell lysates were analyzed for DPP1, NE, Pr3, and CatG activities using specific inhibitors and synthetic peptide substrates in 384-well plates. [1]

0.2, 2, and 20 mg/kg/day; oral
Naive rats

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An in vivo study was performed in naïve rats. Rats were dosed orally twice daily with Brensocatib at 0.2, 2, and 20 mg/kg/day for eight days. At termination, bone marrow was collected by femoral aspiration for NSP activity analysis using commercial synthetic peptide substrates. [1]
Rat and dog pharmacokinetic studies were conducted. For rat PK, doses were 1 mg/kg intravenous and 3 mg/kg oral. For dog PK, doses were 1 mg/kg intravenous and 2 mg/kg oral. [1]

Brensocatib exhibited good metabolic stability in human liver microsomes (HLM CLint <14 µL/min/mg) and human, rat, and canine hepatocytes (CLint <3.5 µL/min/10^6 cells). [1]
The binding rate to human plasma proteins was 87%, 94% in rats, and 70% in dogs. [1]
The kinetic solubility at pH 7.4 was 180 µM. The LogD value at pH 7.4 was 0.8. [1]
The apparent permeability (Papp) of Caco-2 cells from A to B was 9.2 x 10^-6 cm/s, and from B to A was 58 x 10^-6 cm/s, with an efflux ratio of 6.3. [1]
In rat pharmacokinetic studies, the clearance (CL) was 1 mL/min/kg, the steady-state volume of distribution (Vss) was 1 L/kg, the terminal half-life (t1/2) was 7 hours, and the oral bioavailability (F%) was 30%. [1]
In canine pharmacokinetic studies, the CL was 8 mL/min/kg, the Vss was 11 L/kg, the t1/2 was 18 hours, and the F% was 92%. [1]
The compound is stable in plasma with a half-life >10 hours. It has a low turnover rate in human hepatocytes and good in vitro-in vivo correlation, indicating that it is suitable for once-daily administration. [1]

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Absorption
Brensocalide is rapidly absorbed after oral administration. The median time to peak plasma concentration (Tmax) after a single dose of 10 mg or 25 mg is 1.0–1.4 hours. The absolute oral bioavailability of brensocalide has not been studied in humans, but based on mass balance studies in healthy subjects, its oral absorption is greater than 80%. The estimated geometric mean Cmax after a once-daily administration of 10 mg or 25 mg brensocalide was 85.4 ng/mL and 259 ng/mL, respectively. In healthy subjects, after reaching steady state, Cmax increased approximately 1.5-fold and AUCtau increased approximately 2-fold compared to a single dose. The presence of food slightly delays the absorption of brensocalide, but does not result in a clinically significant difference in exposure.
Elimination Pathway
Following a single oral administration of radiolabeled brensocalide in healthy subjects, 54.2% of the dose was recovered in urine (22.8% of which was unchanged brensocalide) and 28.3% of the dose was recovered in feces (2.4% of which was unchanged brensocalide). Current data indicate that renal impairment does not significantly affect the clearance and systemic exposure of brensocalide, suggesting that no dose adjustment is necessary for patients with renal impairment.
Volume of Distribution
In patients with NCFB, the steady-state estimated volume of distribution after once-daily administration of 10 mg or 25 mg brensocalide is 126 to 138 L.
Clearance
The apparent oral clearance of brensocalide is 6.4 to 10.7 L/h. In a study of healthy Japanese and Caucasian subjects, the mean steady-state CL/F in Japanese subjects (10.1, 6.4, and 10.7 L/h in the 10 mg, 25 mg, and 40 mg groups, respectively) was slightly higher than that in Caucasian subjects (8.5, 7.0, and 6.5 L/h, respectively).
Protein Binding
Brensocalide is 87.2% bound to protein in human plasma. Metabolites/Metabolites
Blensocarte is primarily metabolized via CYP3A, with minor amounts metabolized via CYP2C8 and CYP2D6. A major circulating metabolite, thiocyanate, has been detected in plasma, accounting for 51% of the total radioactivity following administration of radiolabeled brlensocarte. In vitro studies have shown that brlensocarte is also a weak inducer of CYP3A.
Biological Half-Life
The elimination half-life of brlensocarte after a single oral dose in healthy subjects is 25 to 39 hours. In a study of healthy Japanese and Caucasian subjects, the elimination half-life of brlensocarte was 22 to 28 hours.

Brensocatib lacks aortic binding ability, as confirmed by in vitro competitive covalent binding assays using rat aortic tissue homogenates and quantitative whole-body autoradiography studies in rats. [1]
In a propionaldehyde reactivity assay, the compound is stable (half-life > 50 h), which is designed to detect its reactivity with aldehydes. [1]
It exhibits weak inhibition of hERG channels, with an IC50 > 33 µM. [1]
The compound demonstrates excellent selectivity in over 200 in vitro assays. [1]

[1]. 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.

Brensocatib is being investigated in the clinical trial NCT03218917 (evaluating the efficacy of INS1007 in patients with noncystic fibrotic bronchiectasis). Brensocatib is a small, reversibly bioavailable, oral-grade dipeptidyl peptidase 1 (DPP1) inhibitor with potential anti-inflammatory activity. After oral administration, Brensocatib reversibly binds to and inhibits DPP1 activity, thereby suppressing the activation of neutrophil serine proteases (NSPs), including neutrophil elastase (NE), during neutrophil maturation. This inhibition of NSP activity may prevent lung inflammation and damage, and improve lung function associated with respiratory diseases induced by NSPs. Serine proteases (NSPs) released by neutrophils during inflammation are upregulated in various respiratory diseases.

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Drug Indication
Treatment of noncystic fibrotic bronchiectasisBrensocatib is a second-generation reversible covalent DPP1 inhibitor that does not have the aortic binding defect compared to first-generation candidates. [1]
It is a highly effective and selective clinical candidate for chronic obstructive pulmonary disease (COPD). [1]
A Phase I clinical trial in humans was initiated in the fourth quarter of 2014. [1]
Its mechanism of action involves the inhibition of DPP1 in the bone marrow, thereby releasing neutrophils that do not contain stored active neutrophil elastase (NE), proteinase-3 (Pr3), or cathepsin G (CatG), which may reduce inflammation and neutrophil-mediated lung injury. [1]
Noncystic fibrotic bronchiectasis (NCFB) is a chronic lung disease characterized by airway dilatation, mucus buildup, and neutrophil inflammation. Brensocatib is a first-in-class dipeptidyl peptidase 1 (DPP1) inhibitor that inhibits neutrophil serine proteases, thereby addressing a key driver of inflammation. It reduces acute exacerbations and slows the decline in lung function, providing a targeted approach to the treatment of NCFB. Brensocatib was approved by the U.S. FDA on August 12, 2025, for the treatment of adult and pediatric patients with NCFB. Brensocatib is a small-molecule, reversible, orally bioavailable dipeptidyl peptidase 1 (DPP1) inhibitor with potential anti-inflammatory activity. After oral administration, brensocatib reversibly binds to and inhibits DPP1 activity, thereby inhibiting the activation of neutrophil serine proteases (NSPs, including neutrophil elastase (NE)) during neutrophil maturation. This inhibition of NSP activity may prevent lung inflammation and damage and improve lung function associated with NSP-induced respiratory diseases. NSPs are serine proteases released by neutrophils during inflammation and are upregulated in various respiratory diseases. Brenzocarbide is a small molecule drug that has completed Phase III clinical trials (covering all indications) and has five investigational indications. It is a cathepsin C inhibitor; its structure is described in the first article. Bronchiectasis is a progressive inflammatory lung disease with diverse clinical presentations and etiologies, but most patients experience chronic cough and sputum production. Neutrophil-driven inflammation exacerbates persistent inflammation, impaired mucociliary clearance, airway damage, and recurrent infections. DPP-1 plays a crucial role in this process, activating excessive neutrophil serine proteases, leading to worsening of the condition, more frequent acute exacerbations, and a faster decline in lung function. The FDA's decision was based on the results of the Phase III ASPEN clinical trial. This study included 1721 patients with bronchiectasis (1680 adults and 41 adolescents) who were randomly assigned to three groups to receive 10 mg brensocatib (n = 583), 25 mg brensocatib (n = 575), or placebo (n = 563). All patients received standard treatment. Compared to placebo, both doses of brensocatib reduced the number of acute pulmonary exacerbations by approximately 20%. Patients receiving the 10 mg dose experienced an average of 1.02 exacerbations per year, those receiving the 25 mg dose experienced an average of 1.04 exacerbations per year, and those receiving placebo experienced an average of 1.29 exacerbations per year. Brensocarb also delayed the time to first exacerbation and increased the proportion of patients exacerbation-free throughout the year (48.5% in both dose groups, compared to 40.3% in the placebo group). The decline in lung function (measured by FEV₁) was significantly lower in the 25 mg dose group (24 mL) than in the placebo group (62 mL), but there was no significant difference between the 10 mg dose group and the placebo group (50 mL). The incidence of severe acute exacerbations was slightly lower with brensocalide, but the difference was not statistically significant. Adverse reactions were similar across groups, but the incidence of mild skin thickening (hyperkeratosis) was higher in the brensocalide groups: 1.4% in the 10 mg group, 3.0% in the 25 mg group, and 0.7% in the placebo group. As the first FDA-approved drug for the treatment of noncystic fibrotic bronchiectasis, brensocalide tablets offer a new option for reducing acute exacerbations and slowing the decline in lung function. Currently, treatment for this disease mainly relies on supportive care (e.g., airway clearance, antibiotics, mucolytic agents), and the approval of brensocalide adds a new approach to the treatment of this chronic progressive lung disease.

C23H24N4O4

420.47

420.18

C, 65.70; H, 5.75; N, 13.33; O, 15.22

1802148-05-5

118253852

Light yellow to yellow solid powder

2.447

2

6

5

31

699

2

CN1C2=C(C=CC(=C2)C3=CC=C(C=C3)C[C@@H](C#N)NC(=O)[C@@H]4CNCCCO4)OC1=O

AEXFXNFMSAAELR-RXVVDRJESA-N

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

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.95 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)