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Synfacts 2020; 16(11): 1273
DOI: 10.1055/s-0040-1706327
Synthesis of Natural Products and Potential Drugs

Synthesis of Brensocatib

Contributor(s):
Philip Kocienski
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.
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Key words

brensocatib - cathepsin C inhibitor - COVID-19 - Suzuki–Miyaura coupling - α-aminonitrile - dehydration

Significance

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.


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Comment

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.


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Publication History

Article published online:
20 October 2020

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