title: Hydantoins, triazolones, and imidazolones as selective non-hydroxamate inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).
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.
authors: Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA. jim.sheppeck@bms.com
authors: James E
authors: JE
authors: Sheppeck
authors: John L
authors: JL
authors: Gilmore
authors: Andrew
authors: A
authors: Tebben
authors: Chu-Biao
authors: CB
authors: Xue
authors: Rui-Qin
authors: RQ
authors: Liu
authors: Carl P
authors: CP
authors: Decicco
authors: James J-W
authors: JJ
authors: Duan
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006827:Hydantoins / Q000737:chemistry / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D006827:Hydantoins; D006877:Hydroxamic Acids; D007093:Imidazoles; D014230:Triazoles; C117197:imidazolone; D051722:ADAM Proteins; D000072198:ADAM17 Protein