Discovery of α-Amidobenzylboronates as Highly Potent Covalent Inhibitors of Plasma Kallikrein

Allison, Matthew; Davie, Rebecca L.; Mogg, Adrian J.; Hampton, Sally L.; Emsley, Jonas; Stocks, Michael J.

Abstract

Hereditary angioedema (HAE), a rare genetic disorder, is associated with uncontrolled plasma kallikrein (PKa) enzyme activity leading to the generation of bradykinin swelling in subcutaneous and submucosal membranes in various locations of the body. Herein, we describe a series of potent α-amidobenzylboronates as potential covalent inhibitors of PKa. These compounds exhibited time-dependent inhibition of PKa (compound 20 IC50 66 nM at 1 min, 70 pM at 24 h). Further compound dissociation studies demonstrated that 20 showed no apparent reversibility comparable to d-Phe-Pro-Arg-chloromethylketone (PPACK) (23), a known nonselective covalent PKa inhibitor.

• Journal Article Type: Article
• Acceptance Date: Mar 26, 2024
• Online Publication Date: Mar 28, 2024
• Publication Date: Apr 11, 2024
• Deposit Date: Mar 31, 2024
• Publicly Available Date: Apr 5, 2024
• Journal: ACS Medicinal Chemistry Letters
• Print ISSN: 1948-5875
• Electronic ISSN: 1948-5875
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Issue: 4
• Pages: 501–509
• DOI: https://doi.org/10.1021/acsmedchemlett.3c00572
• Keywords: Plasma kallikrein, Serine protease, Covalent inhibitor, Boronates
• Public URL: https://nottingham-repository.worktribe.com/output/33028208
• Publisher URL: https://pubs.acs.org/doi/10.1021/acsmedchemlett.3c00572