Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates.
A series of thiomorpholine sulfonamide hydroxamate TACE inhibitors, all bearing propargylic ether P1' groups, was explored. In particular, compound 5h has excellent in vitro potency against isolated TACE enzyme and in cells, oral activity in a model of TNF-alpha production and a collagen-induced arthritis model, was selected as a clinical candidate for the treatment of RA.
Levin
J I
JI
Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. levinji@wyeth.com
Chen
J M
JM
Laakso
L M
LM
Du
M
M
Schmid
J
J
Xu
W
W
Cummons
T
T
Xu
J
J
Jin
G
G
Barone
D
D
Skotnicki
J S
JS
D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000114:Acetylene / Q000737:chemistry*; D000284:Administration, Oral; D000480:Alkynes / Q000737:chemistry; D000818:Animals; D001168:Arthritis / Q000188:drug therapy; D018938:Caco-2 Cells; D003094:Collagen / Q000633:toxicity; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D000882:Haplorhini; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry; D008070:Lipopolysaccharides / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry; D020005:Propanols / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000480:Alkynes; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; D009025:Morpholines; D020005:Propanols; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C028971:thiamorpholine; D003094:Collagen; C028255:propargyl alcohol; D051722:ADAM Proteins; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; C507083:Mmp13 protein, rat; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; C000606464:Adam17 protein, rat; D000114:Acetylene