A new study reports the discovery and optimization of a series of orally available, potent plasma kallikrein inhibitors (PKaI) for potential use with patients with hereditary angioedema (HAE).

The study, reported in Bioorganic and Medicinal Chemistry, used a detailed lead optimization process that identified a lead compound as a potent inhibitor.

“We have recently reported the discovery of Berotralstat (BCX7353), a once-daily orally bioavailable small-molecule PKal inhibitor for the prophylactic treatment of HAE in patients 12 years and older,” the authors wrote. “Herein, we report the discovery and optimization of a series of small molecules containing quaternary carbons that act as potent and orally bioavailable PKal inhibitors.”

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HAE is the result of mutations in the SERPING1 gene, which encodes the C1 esterase inhibitor. This inhibitor blocks PKal activity, which is the main instigator of vascular swelling and therefore of HAE attacks. PKaI inhibition is a current prophylactic therapeutic strategy for HAE, and to date, most approved treatments that act on this pathway are administered by injection. An oral prophylactic therapy would increase convenience and reduce the treatment burden for patients, thereby improving their quality of life.  

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Small-molecule medicinal drugs have been found to be more effective, stable, and potent if they have quaternary carbons as part of their structure, which afford them a 3-dimensional shape as opposed to flat planar molecules. The research team designed a series of small PKaI-inhibitor molecules with quaternary carbons and conducted a series of experiments demonstrating their improved potency and targeting ability in rat models of HAE.

In particular, the authors assessed various substitution opportunities in the molecules bearing a quaternary carbon and arrived at “lead compound 37,” which was both potent and showed an improved pharmacokinetic profile compared with their other PKaI inhibitor compounds when administered to rats.


Zhang W, Vadlakonda S, Wu M, et al. Discovery and optimization of orally bioavailable and potent plasma Kallikrein inhibitors bearing a quaternary carbon. Bioorg Med Chem. 2022 Nov 1;73:117035. doi:10.1016/j.bmc.2022.117035