AZD5248

AZD5248 is an orally active, selective dipeptidyl peptidase 1 (cathepsin C) inhibitor, with IC₅₀ values of 1 nM and 17 nM against human CatC, 44 nM against human DPP1, and 67 nM against rat DPP1. It exhibits low clearance and high bioavailability in animal models. AZD5248 forms an irreversible covalent bond with the catalytic Cys234 residue of CatC, exerts reversible inhibition via its nitrile moiety, blocks CatC-dependent amyloid formation, and reduces the activation levels of neutrophil serine proteases in bone marrow and blood. AZD5248 reacts with aortic elastin aldehydes to form stable 4-imidazolinones, induces ultrastructural changes in aortic tissue, and has an α-amino acid-based backbone. AZD5248 reduces the severity of acute pancreatitis in mouse models. AZD5248 can be used in research on chronic obstructive pulmonary disease, acute pancreatitis, neurodegenerative diseases, lysosomal storage disorders, acute lung injury, cystic fibrosis, and neutrophil-mediated inflammatory diseases^{[1][2][3][4][5]}. In Vitro:AZD5248 (1-10 μM) potently inhibits recombinant human Cathepsin C with an enzyme IC₅₀ of 1 nM^[1].
AZD5248 exhibits fast reactivity in an in vitro propionaldehyde assay, with 15% remaining after 1 h incubation and a half-life of 0.36 h, indicating aortic binding liability^[1].
AZD5248 (Serial dilutions; 3 hours) potently inhibits recombinant human Cathepsin C with an IC₅₀ of 2.9 nM^[2].
AZD5248 binds to the active site of human Cathepsin C, as evidenced by its co-crystal structure with the protein, and shares overlapping binding space with compound 54 in the enzyme's active site^[3].
AZD5248 (50-100 μM; 18 h) shows high reactivity with model aldehydes in pH 7.4 phosphate buffer at 37 °C, with a half-life of 39 min for reaction with 5 mM propionaldehyde^[4].
AZD5248 (100 μM; overnight preincubation, 2 h incubation) competitively inhibits ¹⁴C]AZD5248 binding to Han Wistar rat aortic homogenate, showing strong activity in this in vitro covalent binding assay^[4].
AZD5248 potently inhibits DPP1, with supporting data indicating high selectivity for the target^[5]. In Vivo:AZD5248 (20 mg/kg; p.o.; twice daily; 6 days) significantly inhibits pancreatic CatC activity and reduces tissue damage in a caerulein-induced acute pancreatitis mouse model^[2].
AZD5248 (20 mg/kg; p.o.; single dose) shows persistent, high-affinity binding to rat aortic tissue, with radioactivity retained in the aorta for at least 21 days after a single oral 20 mg/kg dose^[4].
AZD5248 (20-200 mg/kg/day; p.o.; daily; 14-28 days) causes ultrastructural changes to rat aortic endothelium and smooth muscle cells, including reduced attachment to elastic laminae and increased intercellular substance^[4].
AZD5248 (10 mg/kg; p.o.; twice daily; 8 days) reduces bone marrow neutrophil serine protease activity by 64-90% in rats^[5].