Structure-Guided Design of Novel, Potent, and Selective Macrocyclic Plasma Kallikrein Inhibitors

A series of macrocyclic analogues were designed and synthesized based on the cocrystal structure of small molecule plasma kallikrein (pKal) inhibitor, <b>2</b>, with the pKal protease domain. This led to the discovery of a potent macrocyclic pKal inhibitor <b>29</b>, with an IC₅₀ of 2 nM for one olefinic isomer and 42.3 nM for the other olefinic isomer.