title: 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.
abstract: 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.
authors.affiliation: Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA. venkata@wyeth.com
authors.forename: Venkatesan
authors.initials: V
authors.lastname: Aranapakam
authors.forename: Jamie M
authors.initials: JM
authors.lastname: Davis
authors.forename: George T
authors.initials: GT
authors.lastname: Grosu
authors.forename: Jannie
authors.initials: J
authors.lastname: Baker
authors.forename: John
authors.initials: J
authors.lastname: Ellingboe
authors.forename: Arie
authors.initials: A
authors.lastname: Zask
authors.forename: Jeremy I
authors.initials: JI
authors.lastname: Levin
authors.forename: Vincent P
authors.initials: VP
authors.lastname: Sandanayaka
authors.forename: Mila
authors.initials: M
authors.lastname: Du
authors.forename: Jerauld S
authors.initials: JS
authors.lastname: Skotnicki
authors.forename: John F
authors.initials: JF
authors.lastname: DiJoseph
authors.forename: Amy
authors.initials: A
authors.lastname: Sung
authors.forename: Michele A
authors.initials: MA
authors.lastname: Sharr
authors.forename: Loran M
authors.initials: LM
authors.lastname: Killar
authors.forename: Thomas
authors.initials: T
authors.lastname: Walter
authors.forename: Guixian
authors.initials: G
authors.lastname: Jin
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cowling
authors.forename: Jeff
authors.initials: J
authors.lastname: Tillett
authors.forename: Weiguang
authors.initials: W
authors.lastname: Zhao
authors.forename: Joseph
authors.initials: J
authors.lastname: McDevitt
authors.forename: Zhang Bao
authors.initials: ZB
authors.lastname: Xu
mesh_terms: 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
chemical_list: 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