Johannesson P.
*
et al.
AstraZeneca Gothenburg, Mölndal, Sweden
Discovery of Second Generation Reversible Covalent DPP1 Inhibitors Leading to an Oxazepane Amidoacetonitrile Based Clinical Candidate (AZD7986).
J. Med. Chem. 2016;
59: 9457-9472
DOI:
10.1021/acs.jmedchem.6b01127
Key words
brensocatib - AZD7986 - dipeptidyl dipeptidase 1 inhibitor - cathepsin C inhibitor - COVID-19
Significance
Cathepsin C (CatC) is a cysteine dipeptidyl amino-peptidase that activates most tissue-degrading elastase-related serine proteases. The highlighted paper describes the discovery of brensocatib (AZD7986), a CatC inhibitor. Brensocatib is now a clinical candidate to impair protease-driven tissue degradation in COVID-19 (B. Korkmaz, A. Lesner, S. Marchand-Adam, C. Moss, D. E. Jenne J. Med. Chem.
2020, 63, 13258).
Comment
While the paper includes some synthetic details, the potential manufacturing route depicted is taken from an earlier patent (WO 2015 110826 A1). The notable feature is the one-pot amidation (E → G) and amide dehydration reactions (G → H) used to construct the amidoacetonitrile moiety.
