Subscribe to RSS
Synthesis of Brensocatib
Discovery of Second Generation Reversible Covalent DPP1 Inhibitors Leading to an Oxazepane Amidoacetonitrile Based Clinical Candidate (AZD7986).
J. Med. Chem. 2016;
Key wordsbrensocatib - cathepsin C inhibitor - COVID-19 - Suzuki–Miyaura coupling - α-aminonitrile - dehydration
Cathepsin C (CatC) is a cysteine dipeptidyl amino-peptidase that activates tissue-degrading elastase-related serine proteases. Brensocatib is a potent reversible CatC inhibitor that was originally developed by AstraZeneca for the treatment of chronic obstructive pulmonary disorder. It is now being evaluated as a treatment for protease-driven respiratory tissue degradation associated with COVID-19 infections (J. Med. Chem. 2020, 63, DOI: 10.1021/acs.jmedchem.0c00776). Brensocatib was granted breakthrough therapy designation by the FDA in 2020 for the treatment of non-cystic fibrosis bronchiectasis.
For a detailed description of the mol-scale synthesis of the fragments A, B, and E and their union see the associated patent (WO 2015 110826). After the Suzuki coupling that assembles biaryl C, α-aminonitrile G was installed by dehydration of α-aminocarboxamide F with T3P (propanephosphonic anhydride). The α-aminonitrile could also be installed by dehydration of B prior to Suzuki coupling.
20 October 2020 (online)
© 2020. Thieme. All rights reserved
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany