The Synthesis of Diphenyl Phosphonate Analogues of α-Amino Acids as Enzyme Inhibitors

Abstract

α-Aminoalkylphosphonic acids are analogues of natural aminoacids and as such have been the subject of much research effort over past years1. The diphenyl esters of α- aminoalkylphosphonic acids are particularly potent and show high selectivity as irreversible inhibitors of serine proteinases. Thus far, α-aminoalkylphosphonic acid ester analogues of a number of aliphatic- and aromatic aminoacids have been prepared including valine, phenylalanine, tryptophan, and tyrosine2, and the basic aminoacids ornithine, lysine. etc.3. We have now also prepared the a-diphenyl phosphonate analogues of the acidic aminoacids, aspartic and glutamic4. These have been examined as potential inactivators of serine proteinases exhibiting a P1 specificity for aspartate and glutamate, e.g. S. aureus V8 protease and granzyme B.