Synthesis and activity of tryptophan sulfonamide derivatives as novel non-hydroxamate TNF-alpha converting enzyme (TACE) inhibitors.
A novel series of non-hydroxamate tryptophan sulfonamide derivatives containing a butynyloxy P1' moiety was identified as inhibitors of TNF-alpha converting enzyme (TACE). The structure-activity relationship of the series was examined via substitution on the tryptophan indole ring. Of the compounds investigated, 2-(4-(but-2-ynyloxy)phenylsulfonamido)-3-(1-(4-methoxybenzyl)-1H-indol-3-yl)propanoic acid (12p) has the best in vitro potency against isolated TACE enzyme with an IC(50) of 80 nM. Compound 12p also shows good selectivity over MMP-1, -13, -14.
Park
Kaapjoo
K
Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. ParkK3@wyeth.com
Gopalsamy
Ariamala
A
Aplasca
Alexis
A
Ellingboe
John W
JW
Xu
Weixin
W
Zhang
Yuhua
Y
Levin
Jeremy I
JI
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C544077:2-(4-(but-2-ynyloxy)phenylsulfonamido)-3-(1-(4-methoxybenzyl)-1H-indol-3-yl)propanoic acid; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D014364:Tryptophan; D051722:ADAM Proteins; D000072198:ADAM17 Protein