Synthesis and structure-activity relationship of N-substituted 4-arylsulfonylpiperidine-4-hydroxamic 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. In our preceding paper, we have reported on a series of novel and orally active N-hydroxy-alpha-phenylsulfonylacetamide derivatives. However, these compounds had two drawbacks (moderate selectivity and chirality issues). To circumvent these two problems, a series of novel and orally active N-substituted 4-benzenesulfonylpiperidine-4-carboxylic acid hydroxyamide derivatives have been synthesized. The present paper deals with the synthesis and SAR of these compounds. Among the several compounds synthesized, derivative 55 turned out to be a potent, selective, and an orally active MMP inhibitor in the clinically relevant advanced rabbit osteoarthritis model. Detailed pharmacokinetics and metabolism data are described.
Aranapakam
Venkatesan
V
Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. venkata@wyeth.com
Davis
Jamie M
JM
Grosu
George T
GT
Baker
Jannie
J
Ellingboe
John
J
Zask
Arie
A
Levin
Jeremy I
JI
Sandanayaka
Vincent P
VP
Du
Mila
M
Skotnicki
Jerauld S
JS
DiJoseph
John F
JF
Sung
Amy
A
Sharr
Michele A
MA
Killar
Loran M
LM
Walter
Thomas
T
Jin
Guixian
G
Cowling
Rebecca
R
Tillett
Jeff
J
Zhao
Weiguang
W
McDevitt
Joseph
J
Xu
Zhang Bao
ZB
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D001681:Biological Assay; D002356:Cartilage / Q000187:drug effects / Q000201:enzymology; D002417:Cattle; D018360:Crystallography, X-Ray; D003956:Dialysis; D004285:Dogs; D000882:Haplorhini; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D051379:Mice; D008958:Models, Molecular; D010003:Osteoarthritis / Q000188:drug therapy*; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
C475429:1-benzyl-4-(4-(4-chlorophenoxy)benzenesulfonyl)piperidine-4-carboxylic acid; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D010880:Piperidines; D011480:Protease Inhibitors; D013450:Sulfones; D051722:ADAM Proteins; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; C507081:Mmp13 protein, mouse; C507083:Mmp13 protein, rat; D000072198:ADAM17 Protein