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

Jan Pascal Kahler; Stijn Lenders; Merel A T van de Plassche; Steven H L Verhelst

doi:10.1021/acsmedchemlett.0c00284

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

ACS Med Chem Lett. 2020 Aug 10;11(9):1739-1744. doi: 10.1021/acsmedchemlett.0c00284. eCollection 2020 Sep 10.

Authors

Jan Pascal Kahler¹, Stijn Lenders¹, Merel A T van de Plassche¹, Steven H L Verhelst^{1

2}

Affiliations

¹ Laboratory of Chemical Biology, Department of Cellular and Molecular Medicine, KU Leuven - University of Leuven, Herestraat 49 Box 802, 3000 Leuven, Belgium.
² AG Chemical Proteomics, Leibniz Institute for Analytical Sciences - ISAS, Otto-Hahn-Str. 6b, 44227 Dortmund, Germany.

Abstract

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.