Anthranilate sulfonamide hydroxamate TACE inhibitors. Part 2: SAR of the acetylenic P1' group.
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing novel acetylenic P1' groups was explored. In particular, compound 4t bearing a butynyloxy P1' moiety has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and oral activity in an in vivo model of TNF-alpha production.
Levin
J I
JI
Wyeth-Ayerst Research, 401N. Middletown Road, Pearl River, NY 10965, USA. levinj@war.wyeth.com
Chen
J M
JM
Du
M T
MT
Nelson
F C
FC
Killar
L M
LM
Skala
S
S
Sung
A
A
Jin
G
G
Cowling
R
R
Barone
D
D
March
C J
CJ
Mohler
K M
KM
Black
R A
RA
Skotnicki
J S
JS
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000114:Acetylene / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D062367:ortho-Aminobenzoates / Q000737:chemistry* / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; D062367:ortho-Aminobenzoates; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; D000114:Acetylene