Synthesis and structure-activity relationship of alpha-sulfonylhydroxamic acids as novel, orally active matrix metalloproteinase inhibitors for the treatment of osteoarthritis.
The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. These enzymes are strictly regulated by endogenous inhibitors such as tissue inhibitors of MMPs and alpha(2)-macroglobulins. Overexpression of these enzymes has been implicated in various pathological disorders such as arthritis, tumor metastasis, cardiovascular diseases, and multiple sclerosis. Developing effective small-molecule inhibitors to modulate MMP activity is one approach to treat these degenerative diseases. The present work focuses on the discovery and SAR of novel N-hydroxy-alpha-phenylsulfonylacetamide derivatives, which are potent, selective, and orally active MMP inhibitors.
Aranapakam
Venkatesan
V
Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. venkata@wyeth.com
Grosu
George T
GT
Davis
Jamie M
JM
Hu
Baihua
B
Ellingboe
John
J
Baker
Jannie L
JL
Skotnicki
Jerauld S
JS
Zask
Arie
A
DiJoseph
John F
JF
Sung
Amy
A
Sharr
Michele A
MA
Killar
Loran M
LM
Walter
Thomas
T
Jin
Guixian
G
Cowling
Rebecca
R
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000284:Administration, Oral; D000818:Animals; D001681:Biological Assay; D002356:Cartilage / Q000187:drug effects / Q000201:enzymology; D002417:Cattle; D003956:Dialysis; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D051379:Mice; D010003:Osteoarthritis / Q000188:drug therapy; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C475428:N-hydroxy-2-(4-methoxybenzenesulfonyl)-2-methyl-3-(4-(2-piperidin-1-ylethoxy)phenyl)propionamide; D011480:Protease Inhibitors; D013450:Sulfones; D051722:ADAM Proteins; D053509:Matrix Metalloproteinase 13; D008666:Metalloendopeptidases; C507081:Mmp13 protein, mouse; C507083:Mmp13 protein, rat; D000072198:ADAM17 Protein