Hydantoins, triazolones, and imidazolones as selective non-hydroxamate inhibitors of tumor necrosis factor-alpha 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.
Sheppeck
James E
JE
Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA. jim.sheppeck@bms.com
Gilmore
John L
JL
Tebben
Andrew
A
Xue
Chu-Biao
CB
Liu
Rui-Qin
RQ
Decicco
Carl P
CP
Duan
James J-W
JJ
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*
D004791:Enzyme Inhibitors; D006827:Hydantoins; D006877:Hydroxamic Acids; D007093:Imidazoles; D014230:Triazoles; C117197:imidazolone; D051722:ADAM Proteins; D000072198:ADAM17 Protein