Brensocatib (AZD7986) is a Dipeptidyl peptidase 1 (DPP1) inhibitor (pIC50s: 6.85, 7.7, 7.6, 7.8, and 7.8 in human, rat, mouse, rabbit, and dog, respectively).

DPP1:pIC50: 6.85(human), DPP1:pIC50: 7.6(mouse), DPP1:pIC50: 7.7(rat), DPP1:pIC50: 7.8(dog), DPP1:pIC50: 7.8(rabbit)

AZD7986在丙醛活性测定中表现稳定，半衰期超过50小时。经AZD7986（38 pM至10 μM）处理后，观察到DPP1及所有三种NSPs（NE、Pr3、CatG）的细胞裂解物酶活性呈浓度依赖性下降。AZD7986以浓度依赖性方式抑制所有三种NSPs的激活，三者的pIC50值均约为7。这种活性降低几乎是完全的，NE、Pr3和CatG的活性在10 μM AZD7986下降至对照的4至10%。

AZD7986在血浆中显示出良好的稳定性，半衰期超过10小时。在体内，AZD7986以剂量依赖的方式抑制了骨髓细胞裂解物中的Pr3和NE的激活，但不抑制CatG的激活。

Activation of neutrophil serine proteases is assessed in vitro using primary bone marrow-derived CD34+ neutrophil progenitor cells. Cells are cultured in media supplemented with rhSCF and rhIL-3 for 7 days, and then for a further 7 days in the presence of G-CSF and different concentrations of AZD7986 (38 pM to 10 μM). After harvesting and lysis with 10% Triton X-100 buffer, cell lysates are kept at -20°C until NSP activity analysis.

Cellular potency is studied using the DPP1-expressing monocytic U937 cell line. Briefly, cells grown in RPMI are plated on 384-well polypropylene v-bottom plates at a density of 5×10^5 cells/mL per well. Added to this is 10 μL of AZD7986 at 37°C for 60 min, followed by 350 μM Gly-Phe-AFC. The well fluorescence is read using a multilabel plate reader. Data are analyzed to calculate pIC50 values.

Rats are used for the in vivo study. Naive rats are dosed orally twice daily with AZD7986 at 0.2, 2, and 20 mg/kg/day for 8 days. At termination, bone marrow is taken by femural aspiration for neutrophil serine proteases activity analysis using commercial synthetic peptide substrates.