Discovery of N-hydroxy-2-(2-oxo-3-pyrrolidinyl)acetamides as potent and selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE).
New inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered using an N-hydroxy-2-(2-oxo-3-pyrrolidinyl)acetamide scaffold. The series was found to be potent in a porcine TACE (pTACE) assay with IC(50)s typically below 5 nM. For most compounds, selectivity for pTACE relative to MMP-1,-2, and -9 is at least 300-fold. Compound 2o was potent in inhibition of TNFalpha production in a human whole blood assay (WBA) with an IC(50) of 0.42 micro M.
Duan
James J-W
JJ
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. james.duan@bms.com
Lu
Zhonghui
Z
Xue
Chu-Biao
CB
He
Xiaohua
X
Seng
Jennifer L
JL
Roderick
John J
JJ
Wasserman
Zelda R
ZR
Liu
Rui-Qin
RQ
Covington
Maryanne B
MB
Magolda
Ronald L
RL
Newton
Robert C
RC
Trzaskos
James M
JM
Decicco
Carl P
CP
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000737:chemistry / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D000081:Acetamides; D004791:Enzyme Inhibitors; D007769:Lactams; D061965:Matrix Metalloproteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human