1254318-44-9
Chemical Structure
AZD5248
- CAS No.: 1254318-44-9
- Formula:C22H22N4O2
- Molecular Weight:374.44
IUPAC Name: (S)-4-amino-N-(1-cyano-2-(4'-cyano-[1,1'-biphenyl]-4-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide
InChIKey: NNUFRZJZOXVZIT-FQEVSTJZSA-N
SMILES: N#CC1=CC=C(C2=CC=C(C[C@H](NC(C3(N)CCOCC3)=O)C#N)C=C2)C=C1
Biological Activity: 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].
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AZD5248 | 98.9% | 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. | ||||||||||||||||||||
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- [1]. Banerjee A, et al. Development of potent and selective Cathepsin C inhibitors free of aortic binding liability by application of a conformational restriction strategy. Bioorg Med Chem Lett. 2021;47:128202. [Content Brief]
- [2]. Hou W, et al. Identification and Optimization of Novel Cathepsin C Inhibitors Derived from EGFR Inhibitors. J Med Chem. 2019;62(12):5901-5919. [Content Brief]
- [3]. Chen X, et al. Discovery and In Vivo Anti-inflammatory Activity Evaluation of a Novel Non-peptidyl Non-covalent Cathepsin C Inhibitor. J Med Chem. 2021;64(16):11857-11885. [Content Brief]
- [4]. Bragg RA, et al. Aortic Binding of AZD5248: Mechanistic Insight and Reactivity Assays To Support Lead Optimzation. Chem Res Toxicol. 2015;28(10):1991-1999. [Content Brief]
- [5]. Chalmers JD, Kettritz R, Korkmaz B. Dipeptidyl peptidase 1 inhibition as a potential therapeutic approach in neutrophil-mediated inflammatory disease. Frontiers in immunology. 2023 Dec 14;14:1239151. [Content Brief]
Keywords
