Peptidyl 3-substituted 1-hydroxyureas as isosteric analogues of succinylhydroxamate MMP inhibitors.
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Campestre C, Tortorella P, Agamennone M, Preziuso S, Biasone A, Nuti E, Rossello A, Gallina C
Peptidyl 3-substituted 1-hydroxyureas as isosteric analogues of succinylhydroxamate MMP inhibitors.
Eur J Med Chem. 2008 May;43(5):1008-14. Epub 2007 Jul 15.
- PubMed ID
- 17719700 [ View in PubMed]
- 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 microM 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) METHYLAMINO-PHENYLALANYL-LEUCYL-HYDROXAMIC ACID Interstitial collagenase IC 50 (nM) 25 N/A N/A Details METHYLAMINO-PHENYLALANYL-LEUCYL-HYDROXAMIC ACID Neutrophil collagenase IC 50 (nM) 0.046 N/A N/A Details