Aliphatic Amines are Viable Pro-drug Moieties in Phosphonoamidate Drugs

Phosphate and phosphonates containing a single P-N bond are frequently used pro-drug motifs to improve cell permeability of these otherwise anionic moieties. Upon entry into the cell, the P-N bond is cleaved by phosphoramidases to release the active agent. Here, we apply a novel mono-amidation strategy to our laboratorys phosphonate-containing glycolysis inhibitor and show that a diverse panel of phosphonoamidates may be rapidly generated for in vitro screening. We show that, in contrast to the canonical L-alanine or benzylamine moieties which have previously been reported as efficacious pro-drug moieties, small aliphatic amines demonstrate greater drug release efficacy for our phosphonate inhibitor. These results expand the scope of possible amine pro-drugs that can be used as second pro-drug leave groups for phosphate or phosphonate-containing drugs. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=42 SRC="FIGDIR/small/026583v1_ufig1.gif" ALT="Figure 1"> View larger version (10K): org.highwire.dtl.DTLVardef@10d953dorg.highwire.dtl.DTLVardef@c10578org.highwire.dtl.DTLVardef@4e0eccorg.highwire.dtl.DTLVardef@ad764f_HPS_FORMAT_FIGEXP M_FIG C_FIG