Acetylenic TACE inhibitors. Part 1. SAR of the acyclic sulfonamide hydroxamates.
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors, all bearing a butynyloxy P1' group, was explored. In particular, compound 5j has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and MMP-9, and oral activity in an in vivo model of TNF-alpha production and a collagen-induced arthritis model.
Levin
J I
JI
Wyeth Research, 401 N Middletown Rd, Pearl River, NY 10965, USA. levinji@wyeth.com
Chen
J M
JM
Cheung
K
K
Cole
D
D
Crago
C
C
Santos
E Delos
ED
Du
X
X
Khafizova
G
G
MacEwan
G
G
Niu
C
C
Salaski
E J
EJ
Zask
A
A
Cummons
T
T
Sung
A
A
Xu
J
J
Zhang
Y
Y
Xu
W
W
Ayral-Kaloustian
S
S
Jin
G
G
Cowling
R
R
Barone
D
D
Mohler
K M
KM
Black
R A
RA
Skotnicki
J S
JS
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000114:Acetylene / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000737:chemistry; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; 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