Brensocatib (AZD7986)

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].

根据细胞实验结果，Brensocatib (AZD7986) 是一种二肽基肽酶 1 (DPP1) 抑制剂，在人、小鼠、大鼠、狗和兔中的 pIC50 值分别为 6.85、7.6、7.7、7.8 和 7.8。在丙醛反应性测试中，brensocatib 表现出稳定性，半衰期超过 50 小时。在 38 pM 至 10 μM Brensocatib 存在下进行分化后，发现 DPP1 和所有三种 nsps 的细胞溶解酶活性（NE、Pr3 和 CatG）出现浓度依赖性降低。 brensocatib 的 pIC50 值约为 7，以浓度依赖性方式抑制所有三种 NSP 的激活。活动水平几乎完全下降。在 10 μM Brensocatib 下，NE、Pr3 和 CatG 的活性降低至对照的 4% 至 10% [1]。

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Brensocatib 是 DPP1 酶和细胞活性的强效、可逆抑制剂。 [1]
在分化中的人原代骨髓来源 CD34+ 中性粒细胞祖细胞中，它能浓度依赖性地抑制中性粒细胞丝氨酸蛋白酶（NE、Pr3、CatG）的激活，对三种 NSPs 的 pIC50 值均在 7 左右，在 10 µM 浓度下将其活性降低至对照的 4-10%。 [1]
该化合物在超过 200 个体外放射性配体结合和酶测定组中显示出高选择性。 [1]

Brensocatib (AZD7986) 的半衰期超过 10 小时，在血浆中表现出良好的稳定性。在体内，brensocatib 剂量依赖性地抑制骨髓细胞裂解物中 NE 和 Pr3 的活化，但不抑制 CatG [1]。

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Brensocatib 以每日两次（0.2、2 和 20 mg/kg/天）的剂量给予初始状态大鼠，持续八天，能剂量依赖性地抑制骨髓细胞裂解物中 NE 和 Pr3 的激活，但对 CatG 无抑制。 [1]

使用基于 384 孔板的荧光测定法评估对分离的人重组 DPP1 酶活性的抑制。化合物在室温下与酶预孵育 30 分钟，然后加入荧光二肽底物 Gly-Arg-AMC。通过拟合数据获得效价数值。 [1]
使用表面等离子体共振直接结合实验 (SPR DBA) 表征结合动力学。相互作用符合 1:1 模型，结合速率 (kon) 为 1.5E+6 (1/Ms)，解离速率 (koff) 为 4.0E-3 (1/s)，pKd 为 8.6，驻留时间（半衰期）为 3 分钟，证实其为可逆抑制剂。 [1]

使用表达 DPP1 的单核细胞 U937 细胞系研究细胞活性。将细胞铺于 384 孔板中，与 DPP1 抑制剂在 37°C 孵育 60 分钟，然后加入底物 Gly-Phe-AFC。使用酶标仪读取荧光值，并计算 pIC50。 [1]
使用人原代骨髓来源 CD34+ 中性粒细胞祖细胞评估对 NSP 激活的影响。细胞在生长培养基中培养七天，然后在 G-CSF 和不同浓度的化合物 30 存在下再培养七天。收集并裂解细胞后，在 384 孔板中使用特异性抑制剂和合成肽底物分析细胞裂解物中的 DPP1、NE、Pr3 和 CatG 活性。 [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 demonstrated good metabolic stability in human liver microsomes (HLM CLint <14 µL/min/mg) and in human, rat, and dog hepatocytes (CLint <3.5 µL/min/10^6 cells). [1]
Plasma protein binding was 87% in human, 94% in rat, and 70% in dog. [1]
Kinetic solubility at pH 7.4 was 180 µM. Measured LogD at pH 7.4 was 0.8. [1]
Caco-2 apparent permeability (Papp) A to B was 9.2 x 10^-6 cm/s, B to A was 58 x 10^-6 cm/s, with an efflux ratio of 6.3. [1]
In rat PK studies, clearance (CL) was 1 mL/min/kg, volume of distribution at steady state (Vss) was 1 L/kg, terminal half-life (t1/2) was 7 hours, and oral bioavailability (F%) was 30%. [1]
In dog PK studies, CL was 8 mL/min/kg, Vss was 11 L/kg, t1/2 was 18 hours, and F% was 92%. [1]
The compound showed good stability in plasma with a half-life >10 hours. The low turnover in human hepatocytes and good in vitro-in vivo correlation predicted suitability for once-daily human dosing. [1]

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Absorption
Brensocatib is rapidly absorbed following oral administration. The median time to maximum plasma concentration (Tmax) is 1.0-1.4 hours after a single dose of 10 mg or 25 mg. The absolute oral bioavailability of brensocatib has not been studied in humans, but based on mass balance studies in healthy subjects, oral absorption is greater than 80%. Following once-daily administration of brensocatib 10 mg or 25 mg, the estimated geometric mean Cmax is 85.4 ng/mL or 259 ng/mL, respectively. In healthy subjects, at steady state, Cmax increased by about 1.5-fold and AUCtau increased by about 2-fold compared to single-dose observations. The presence of food slightly delays the absorption of brensocatib, but does not result in clinically relevant differences in exposure.

Route of Elimination
Following administration of a single oral dose of radiolabeled brensocatib to healthy subjects, 54.2% of the dose was recovered in urine (22.8% as unchanged brensocatib) and 28.3% of the dose was recovered in feces (2.4% as unchanged brensocatib). Available data do not indicate a significant effect of renal impairment on brensocatib elimination and systemic exposure, suggesting that dose adjustment is not necessary in participants with renal impairment.

Volume of Distribution
Following once-daily administration of 10 mg or 25 mg brensocatib in patients with NCFB, the estimated volume of distribution at steady state ranged from 126 to 138 L.

Clearance
The apparent oral clearance of brensocatib ranged from 6.4 to 10.7 L/hour. In a study of healthy Japanese and White adults, mean steady-state CL/F was slightly higher in Japanese participants (10.1, 6.4, and 10.7 L/h for 10 mg, 25 mg, and 40 mg groups, respectively) compared with White participants (8.5, 7.0, and 6.5 L/h).

Protein Binding
The protein binding of brensocatib in human plasma was 87.2%.

Metabolism / Metabolites
Brensocatib is primarily metabolized by CYP3A and to a lesser extent by CYP2C8 and CYP2D6. One major circulating metabolite, thiocyanate, was identified in plasma and accounted for 51% of the total radioactivity following administration of a radio-labeled brensocatib dose. In vitro studies indicate that brensocatib is also a weak inducer of CYP3A.

Biological Half-Life
Following a single oral administration of brensocatib in healthy subjects, the elimination half-life ranged from 25 to 39 hours. In a study of healthy Japanese and White adults, the elimination half-life of brensocatib ranged from 22 to 28 hours.

Brensocatib was free from aortic binding liability, as confirmed by an in vitro competitive covalent binding assay using rat aortic tissue homogenate and a rat quantitative whole-body autoradiography study. [1]
It was stable in the propionaldehyde reactivity assay (half-life >50 hours), designed to detect reactivity with aldehyde functions. [1]
Inhibition of the hERG channel was weak, with an IC50 >33 µM. [1]
The compound showed excellent selectivity in a broad panel of 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 under investigation in clinical trial NCT03218917 (Assessment of INS1007 in Subjects With Non-cystic Fibrosis Bronchiectasis).
Brensocatib is an orally bioavailable, small molecule, reversible inhibitor of dipeptidyl peptidase 1 (DPP1), with potential anti-inflammatory activity. Upon oral administration, brensocatib reversibly binds to and inhibits the activity of DPP1, thereby inhibiting the activation of neutrophil serine proteases (NSPs), including neutrophil elastase (NE), during neutrophil maturation. This inhibits the activity of NSPs, and may prevent lung inflammation and injury and improve lung function associated with NSPs-induced respiratory diseases. NSPs, serine proteases released by neutrophils during inflammation, is upregulated in a number of respiratory diseases.

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Drug Indication
Treatment of non-cystic fibrosis bronchiectasis

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Brensocatib is a second-generation, reversible covalent DPP1 inhibitor discovered to be free from the aorta binding liabilities found in a first-generation candidate. [1]
It is a highly potent, selective clinical candidate for chronic obstructive pulmonary disease (COPD). [1]
Human phase 1 studies were started in the fourth quarter of 2014. [1]
The mechanism of action involves inhibition of DPP1 in the bone marrow, leading to the release of neutrophils without stored active neutrophil elastase (NE), proteinase-3 (Pr3), or cathepsin G (CatG), thereby potentially reducing inflammation and neutrophil-driven lung damage. [1]

Non-cystic fibrosis bronchiectasis (NCFB) is a chronic lung disease characterized by airway widening, mucus accumulation, and neutrophilic inflammation. Brensocatib is a first-in-class dipeptidyl peptidase 1 (DPP1) inhibitor that inhibits neutrophil serine proteases, addressing a key driver of this inflammation. It reduces exacerbations and slows lung function decline, offering a targeted approach to managing NCFB. Brensocatib was approved by the US FDA on August 12, 2025, for use in adults and pediatric patients with NCFB.
Brensocatib is an orally bioavailable, small molecule, reversible inhibitor of dipeptidyl peptidase 1 (DPP1), with potential anti-inflammatory activity. Upon oral administration, brensocatib reversibly binds to and inhibits the activity of DPP1, thereby inhibiting the activation of neutrophil serine proteases (NSPs), including neutrophil elastase (NE), during neutrophil maturation. This inhibits the activity of NSPs, and may prevent lung inflammation and injury and improve lung function associated with NSPs-induced respiratory diseases. NSPs, serine proteases released by neutrophils during inflammation, is upregulated in a number of respiratory diseases.
BRENSOCATIB is a small molecule drug with a maximum clinical trial phase of III (across all indications) and has 5 investigational indications.
a cathepsin C inhibitor; structure in first source

Bronchiectasis is a progressive inflammatory lung disease with variable clinical manifestations and causes, but most patients with the condition experience chronic cough and sputum production. Neutrophil-driven inflammation fuels persistent inflammation, impaired mucociliary clearance, airway damage, and recurrent infection. DPP-1 plays a critical role in this process, activating excess neutrophil serine proteases that contribute to worsening disease severity, more frequent exacerbations, and faster lung function decline.
The FDA based its decision on the results from the Phase 3 ASPEN clinical trial. The study enrolled 1,721 patients (1,680 adults and 41 adolescents) with bronchiectasis and randomized them to receive brensocatib 10 mg (n = 583), brensocatib 25 mg (n = 575), or placebo (n = 563) in addition to standard of care.
Both doses of brensocatib reduced the number of pulmonary exacerbations compared to placebo by about 20%. Patients on 10 mg averaged 1.02 exacerbations per year, those on 25 mg averaged 1.04, and those on placebo averaged 1.29. Brensocatib also delayed the time to the first flare-up and increased the percentage of patients who stayed flare-up-free for the whole year (48.5% with either dose vs. 40.3% with placebo). Lung function (measured by FEV₁) declined significantly less with the 25 mg dose (24 mL) than with placebo (62 mL), but the 10 mg dose did not show a meaningful difference from placebo (50 mL). Severe exacerbations were slightly less common with brensocatib, but the difference was not statistically significant.
Adverse effects were similar between groups, but mild skin thickening (hyperkeratosis) was more common with brensocatib, occurring in 1.4% of patients on 10 mg, 3.0% on 25 mg, and 0.7% on placebo.
As the first FDA-approved therapy for non-cystic fibrosis bronchiectasis, brensocatib tablets provide an option shown to reduce exacerbations and slow lung function decline. With treatment currently relying on supportive treatments (eg, airway clearance, antibiotics, mucoactive agents), its approval adds a new tool to the management 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

109.29

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.95 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (5.95 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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