title: 5'-Phenyl-3'H-spiro[indoline-3,2'-[1,3,4]thiadiazol]-2-one inhibitors of ADAMTS-5 (aggrecanase-2).
abstract: 5'-Phenyl-3'H-spiro[indoline-3,2'-[1,3,4]thiadiazol]-2-one inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared via commercially available starting materials. Selected compounds 23, 33-35 show sub-micromolar ADAMTS-5 potency and strong SAR trends with selectivity over the related metalloproteases ADAMTS-4 (Aggrecanase-1), MMP12, and MMP13. This series of compounds represents progress toward a selective ADAMTS-5 inhibitor as a disease modifying osteoarthritis drug.
authors.affiliation: Exploratory Medicinal Chemistry, Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA. Bursavm@wyeth.com
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Bursavich
authors.forename: Adam M
authors.initials: AM
authors.lastname: Gilbert
authors.forename: Sabrina
authors.initials: S
authors.lastname: Lombardi
authors.forename: Katy E
authors.initials: KE
authors.lastname: Georgiadis
authors.forename: Erica
authors.initials: E
authors.lastname: Reifenberg
authors.forename: Carl R
authors.initials: CR
authors.lastname: Flannery
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Morris
mesh_terms: D010450:Endopeptidases / Q000378:metabolism*; D007211:Indoles / Q000737:chemistry*; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology