A fluorine scan of non-peptidic inhibitors of neprilysin: Fluorophobic and fluorophilic regions in an enzyme active site

This article describes the synthesis and in vitro biological affinities of (poly)fluorinated neprilysin inhibitors. Two series of inhibitors with F-substitution of the central benzimidazole platform of the ligands and the benzylic vector to fill the S1’ pocket of NEP were investigated. The S1’ pocket was found to be highly fluorophobic, and F-substitution led to significantly decreased binding affinities of inhibitors. This result is explained by electrostatically unfavorable close contacts of organic fluorine with the negatively polarized π-surfaces of surrounding aromatic amino acid side chains. In contrast, the protein environment around the benzimidazole platform, with three electropositive guanidinium side chains of Arg residues, was found to provide a fluorophilic environment. Overall, the data support that organic fluorine, with its high negative charge density prefers to orient into electropositive regions of receptor sites. pKa measurements of fluorinated ligands provided several simple patterns for the prediction of pKa values of benzimidazoles, important building blocks in medicinal chemistry.

A series of fluorinated inhibitors of the metalloprotease neprilysin (NEP) was prepared. The arginine-rich protein environment around the central platform of the inhibitor was found to tolerate fluorine substituents well, whereas fluorination of ligand fragments filling the S1’ pocket led to significantly lower binding affinities.Figure optionsDownload as PowerPoint slide