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

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.

Graphical abstractWe have discovered novel hydantoins, triazolones, and imidazolones that are druglike, non-hydroxamate inhibitors of the Zn-metalloprotease TACE with nM potency. Synthesis, SAR, and MMP selectivity of these inhibitors is described and how they conform to a pharmacophore model of heterocyclic non-hydroxamate TACE inhibitors compared with the IK682-TACE X-ray crystal structure.Figure optionsDownload full-size imageDownload as PowerPoint slide