title: 5-((1H-pyrazol-4-yl)methylene)-2-thioxothiazolidin-4-one inhibitors of ADAMTS-5.
abstract: A series of 5-((1H-pyrazol-4-yl)methylene)-2-thioxothiazolidin-4-one inhibitors of ADAMTS-5 (aggrecanase-2) is described. These compounds show microM functional inhibition of ADAMTS-5, and represent a new class of agents with the potential of inhibiting degradation of aggrecan, a major component of cartilage which is lost in osteoporosis. Compound 12 is noteworthy in that it has an ADAMTS-5 IC50: 1.1 microM and shows >40-fold functional selectivity over ADAMTS-4 (aggrecanase-1).
authors.affiliation: Exploratory Medicinal Chemistry, Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA. gilbera@wyeth.com
authors.forename: Adam M
authors.initials: AM
authors.lastname: Gilbert
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Bursavich
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: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D053674:Aggrecans / Q000187:drug effects / Q000378:metabolism; D002356:Cartilage; D006801:Humans; D020128:Inhibitory Concentration 50; D010024:Osteoporosis / Q000188:drug therapy; D011348:Procollagen N-Endopeptidase; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D053674:Aggrecans; D045162:Thiazolidinediones; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human