Synthesis and structure-activity relationship of a novel, non-hydroxamate series of TNF-alpha converting enzyme inhibitors.
A novel series of TNF-alpha converting enzyme (TACE) inhibitors which are non-hydroxamate have been discovered. These compounds use a triazolethione moiety as the zinc binding ligand and exhibit IC50 values from 1.5 to 100 nM in a porcine TACE assay. They also have excellent selectivities over other MMPs.
Gilmore
John L
JL
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. john.gilmore@bms.com
King
Bryan W
BW
Asakawa
Naoyuki
N
Harrison
Kimberly
K
Tebben
Andrew
A
Sheppeck
James E
JE
Liu
Rui-Qin
RQ
Covington
Maryanne
M
Duan
James J-W
JJ
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D051722:ADAM Proteins; D000072198:ADAM17 Protein