| Summary: | Hereditary angioedema (HAE), a rare genetic disorder, is associated with uncontrolled plasma kallikrein (PKa) enzyme activity leading to often severe bradykinin-induced swelling in subcutaneous and submucosal membranes in various locations of the body.
This thesis describes a series of α-amidobenzylboronates (n=7) as highly potent covalent inhibitors of PKa. These compounds exhibited time-dependent inhibition of PKa, with the most potent compound, 91, showing IC50 = 66 nM at 1 min, 70 pM at 24 hours. Further compound dissociation studies demonstrated no apparent reversibility comparable to D-Phe-Pro-Arg-chloromethyl ketone (PPACK), a known non-selective covalent PKa inhibitor. Comparison with noncovalent matched pair analogues (n=8) supported the notion of covalent inhibition. Biological evaluation of α-amidobenzylboronates against closely related proteases; FXIIa, FXIa, plasmin, thrombin, and trypsin showed at least 1000-fold specificity towards PKa in the case of each evaluated compound, demonstrating the first selective covalent inhibitors of PKa.
β-ketobenzylboronates were also synthesised (n=2) and showed moderate activity in PKa however no evidence of covalent inhibition was demonstrated from analysis of enzyme binding kinetics and subjection to jump dilution. Lack of covalent binding notwithstanding, compound 125b showed moderate noncovalent activity in PKa (IC50 = 39 nM). Furthermore, β ketonitrile compounds (n=2) were explored, with one example, compound 129b, showing apparent covalent inhibition of PKa (IC50 = 223 nM at 1 min, 33 nM at 60 min)
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