Peptidyl 3-substituted 1-hydroxyureas as isosteric analogues of succinylhydroxamate MMP inhibitors.

Abstract To evaluate N -hydroxyurea as zinc binding group in the design of MMP inhibitors, two peptidyl 1-hydroxyureas were prepared by N -hydroxycarbamoylation of the diastereomeric dipeptides H-Leu-Phe-NHMe and H- d -Leu-Phe-NHMe. Peptidyl 1-hydroxyureas were more potent than the parent peptides, but dramatically weaker (4–5 orders of magnitude) than the isosteric ( R )-succinylhydroxamate analogue, which displays IC 50 in the range of nM vs MMP-1, -3, -7 and sub-nM vs MMP-2, -8, and -9. The peptidyl 1-hydroxyurea 1a attained an IC 50 of 20 μM vs MMP-9, and substantially approaches inhibition of known N -hydroxyureas based on aminoacids or peptides against other zinc metalloenzymes and non-peptidic N -hydroxyureas against MMPs. Strong preference of the O–N1–C O unit for the antiperiplanar amide bond conformation seems to be the major limit for more effective zinc chelation. Methylation of a peptidyl 1-hydroxyurea at N3, to promote the synperiplanar O–N1–C O conformation required for zinc chelation and improve affinity, resulted in release of a methylimidazolidine-2,4-dione through an undesired intramolecular reaction reminiscent of the Edman peptide degradation.