Acetylenic TACE inhibitors. Part 2: SAR of six-membered cyclic sulfonamide hydroxamates.
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing a butynyloxy P1' group was explored. In particular, compound 5k has excellent in vitro potency against TACE enzyme and in cells, and oral activity in an in vivo model of TNF-alpha production and a collagen-induced arthritis model.
Levin
J I
JI
Wyeth Research, 401N. Middletown Road, Pearl River, NY 10965, USA. levinji@wyeth.com
Chen
J M
JM
Laakso
L M
LM
Du
M
M
Du
X
X
Venkatesan
A M
AM
Sandanayaka
V
V
Zask
A
A
Xu
J
J
Xu
W
W
Zhang
Y
Y
Skotnicki
J S
JS
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000818:Animals; D001682:Biological Availability; D061945:Caspase Inhibitors; D002460:Cell Line; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D009000:Monocytes; D051381:Rats; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000187:drug effects
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; C000606464:Adam17 protein, rat