Discovery of selective hydroxamic acid inhibitors of tumor necrosis factor-alpha converting enzyme.
Modification of the P(1)' substituent of macrocyclic matrix metalloproteinase (MMP) inhibitors provided compounds that are selective for inhibition of tumor necrosis factor-alpha converting enzyme (TACE) over MMP-1 and MMP-2. Several analogues potently inhibited the release of TNF-alpha in a THP-1 cellular assay. Compounds containing a trimethoxyphenyl group in the P(1)' substituent demonstrated TACE selectivity across several series of hydroxamate-based inhibitors.
Holms
J
J
Cancer Research Area, Abbott Laboratories, Dept. 47J, Bldg. AP10, 100 Abbott Park Road, Abbott Park, IL 60064, USA. james.holms@abbott.com
Mast
K
K
Marcotte
P
P
Elmore
I
I
Li
J
J
Pease
L
L
Glaser
K
K
Morgan
D
D
Michaelides
M
M
Davidsen
S
S
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein