Hydantoins, triazolones, and imidazolones as selective non-hydroxamate inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).

Article Details

Citation

Sheppeck JE 2nd, Gilmore JL, Tebben A, Xue CB, Liu RQ, Decicco CP, Duan JJ

Hydantoins, triazolones, and imidazolones as selective non-hydroxamate inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).

Bioorg Med Chem Lett. 2007 May 15;17(10):2769-74. Epub 2007 Mar 3.

PubMed ID
17368021 [ View in PubMed
]
Abstract

We have discovered selective and potent inhibitors of TACE that replace the common hydroxamate zinc binding group with a hydantoin, triazolone, and imidazolone heterocycle. These novel heterocyclic inhibitors of a zinc metalloprotease were designed using a pharmacophore model that we previously described while developing hydantoin and pyrimidinetrione (barbiturate) inhibitors of TACE. The potency and binding orientation of these inhibitors is discussed and they are modeled into the X-ray crystal structure of TACE and compared to hydroxamate and earlier hydantoin TACE inhibitors which share the same 4-[(2-methyl-4-quinolinyl)methoxy]benzoyl P1' group.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
(2R)-N-HYDROXY-2-[(3S)-3-METHYL-3-{4-[(2-METHYLQUINOLIN-4-YL)METHOXY]PHENYL}-2-OXOPYRROLIDIN-1-YL]PROPANAMIDEDisintegrin and metalloproteinase domain-containing protein 17IC 50 (nM)1N/AN/ADetails