title: Identification of potent and selective hydantoin inhibitors of aggrecanase-1 and aggrecanase-2 that are efficacious in both chemical and surgical models of osteoarthritis.
abstract: A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are zinc metalloproteases commonly referred to as aggrecanase-1 and aggrecanase-2, respectively. These enzymes are involved in the degradation of aggrecan, a key component of cartilage. Inhibitors of these enzymes could be potential osteoarthritis (OA) therapies. A series of hydantoin inhibitors of ADAMTS-4 and ADAMTS-5 were identified from a screening campaign and optimized through structure-based drug design to give hydantoin 13. Hydantoin 13 had excellent selectivity over other zinc metalloproteases such as TACE, MMP2, MMP3, MMP13, and MMP14. The compound also produced efficacy in both a chemically induced and surgical model of OA in rats.
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center , Indianapolis, Indiana 46285, United States.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Durham
authors.forename: Valentine J
authors.initials: VJ
authors.lastname: Klimkowski
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rito
authors.forename: Jothirajah
authors.initials: J
authors.lastname: Marimuthu
authors.forename: James L
authors.initials: JL
authors.lastname: Toth
authors.forename: Chin
authors.initials: C
authors.lastname: Liu
authors.forename: Jim D
authors.initials: JD
authors.lastname: Durbin
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Stout
authors.forename: Lisa
authors.initials: L
authors.lastname: Adams
authors.forename: Craig
authors.initials: C
authors.lastname: Swearingen
authors.forename: Chaohua
authors.initials: C
authors.lastname: Lin
authors.forename: Mark G
authors.initials: MG
authors.lastname: Chambers
authors.forename: Kannan
authors.initials: K
authors.lastname: Thirunavukkarasu
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wiley
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D000818:Animals; D001572:Benzofurans / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D006827:Hydantoins / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008592:Menisci, Tibial / Q000187:drug effects / Q000473:pathology; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008953:Models, Anatomic; D008958:Models, Molecular; D015394:Molecular Structure; D010003:Osteoarthritis / Q000188:drug therapy* / Q000473:pathology; D011348:Procollagen N-Endopeptidase / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013329:Structure-Activity Relationship; D000070600:Tibial Meniscus Injuries
chemical_list: D001572:Benzofurans; D006827:Hydantoins; C000595874:N-((4-(1-methylimidazol-2-yl)-2,5-dioxoimidazolidin-4-yl)methyl)-5-(trifluoromethyl)benzofuran-2-carboxamide; D011480:Protease Inhibitors; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C518696:Adamts5 protein, rat; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein