1. Academic Validation
  2. Discovery of α-Amidobenzylboronates as Highly Potent Covalent Inhibitors of Plasma Kallikrein

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

  • ACS Med Chem Lett. 2024 Mar 28;15(4):501-509. doi: 10.1021/acsmedchemlett.3c00572.
Matthew Allison 1 Rebecca L Davie 2 Adrian J Mogg 2 Sally L Hampton 2 Jonas Emsley 1 Michael J Stocks 1
Affiliations

Affiliations

  • 1 Biodiscovery Institute, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, United Kingdom.
  • 2 KalVista Pharmaceuticals Limited, Salisbury, SP4 0BF, United Kingdom.
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.

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