Facile Synthesis of Aminomethyl Phosphinate Esters as Serine Protease Inhibitors with Primed Site Interaction.

Serine proteases comprise about one-third of all proteases, and defective regulation of serine proteases is involved in numerous diseases. Therefore, serine protease inhibitors are promising drug candidates. Aminomethyl diphenyl phosphonates have been regularly used as scaffolds for covalent serine protease inhibition and the design of activity-based probes. However, they cannot make use of a protease's primed site. Therefore, we developed a facile two-step synthesis toward a set of phenyl phosphinates, which is a related scaffold but can interact with the primed site. We tested their inhibitory activity on five different serine proteases and found that a phenyl group directly attached to the phosphorus atom leads to superior activity compared with phosphonates.