Structure-activity relationship of diaryl phosphonate esters as potent irreversible dipeptidyl peptidase IV inhibitors

The previously reported diphenyl 1-(S)-prolylpyrrolidine-2(R,S)-phosphonate (5) was used as a lead compound for the development of potent and irrevers ible inhibitors of dipeptidyl peptidase IV (DPP IV, EC 3.4.14.5). The synth esis of a series of diaryl 1-(S)-prolylpyrrolidine-2(R,S)- phosphonates wit h different substituents on the aryl rings (hydroxyl, methoxy, acylamino, s ulfonylamino, ureyl, methoxycarbonyl, and alkylaminocarbonyl) started from the corresponding phosphites. A good correlation was found between the elec tronic properties of the substituent and the inhibitory activity and stabil ity. The most striking divergence of this correlation was the high potency combined with a high stability of the 4-acetylamino-substituted derivative Ile. This compound shows low cytotoxicity in human peripheral blood mononuc lear cells and also has favorable properties in vivo. Therefore bis(4-aceta midophenyl) 1-(S)-prolylpyrrolidine-2(R,S)-phosphonate (Ile) is considered as a major improvement and will be a highly valuable DPP TV inhibitor for f urther studies on the biological function of the enzyme and the therapeutic value of its inhibition.