Rapid parallel synthesis of dipeptide diphenyl phosphonate esters as inhibitors of dipeptidyl peptidases

In this paper, we present a parallel synthesis of several series of dipeptide diphenyl phosphonates that are known to be irreversible inhibitors of serine proteases. Polymer-assisted solution-phase synthesis (PASP) is used for the rapid and clean coupling between various alpha-aminoalkyl diphenyl phosphonate ester building blocks and commercially available or easily accessible amino acids. These compounds were used for the rapid profiling of dipeptidyl peptidase 11 (DPP 11) and the closely related dipeptidyl peptidase IV (DPP IV). A highly selective DPP 11 inhibitor was identified, N-cyclopentylglycyl-NHCH(C6H5)PO(OPh)(2) (9.35), that will be useful to discriminate between DPP 11 and DPP IV in biological systems in order to further elucidate the biological function of DPP II.