title: Discovery and evaluation of a non-Zn chelating, selective matrix metalloproteinase 13 (MMP-13) inhibitor for potential intra-articular treatment of osteoarthritis.
abstract: Osteoarthritis (OA) is a nonsystemic disease for which no oral or parenteral disease-modifying osteoarthritic drug (DMOAD) is currently available. Matrix metalloproteinase 13 (MMP-13) has attracted attention as a target with disease-modifying potential because of its major role in tissue destruction associated with OA. Being localized to one or a few joints, OA is amenable to intra-articular (IA) therapy, which has distinct advantages over oral therapies in terms of increasing therapeutic index, by maximizing drug delivery to cartilage and minimizing systemic exposure. Here we report on the synthesis and biological evaluation of a non-zinc binding MMP-13 selective inhibitor, 4-methyl-1-(S)-({5-[(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)carbamoyl]pyrazolo[1,5-a]pyrimidine-7-carbonyl}amino)indan-5-carboxylic acid (1), that is uniquely suited as a potential IA-DMOAD: it has long durability in the joint, penetrates cartilage effectively, exhibits nearly no detectable systemic exposure, and has remarkable efficacy.
authors.affiliation: Alantos Pharmaceuticals AG, Im Neuenheimer Feld 584, D-69120 Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Gege
authors.forename: Bagna
authors.initials: B
authors.lastname: Bao
authors.forename: Harald
authors.initials: H
authors.lastname: Bluhm
authors.forename: Jürgen
authors.initials: J
authors.lastname: Boer
authors.forename: Brian M
authors.initials: BM
authors.lastname: Gallagher
authors.forename: Brian
authors.initials: B
authors.lastname: Korniski
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Powers
authors.forename: Christoph
authors.initials: C
authors.lastname: Steeneck
authors.forename: Arthur G
authors.initials: AG
authors.lastname: Taveras
authors.forename: Vijaykumar M
authors.initials: VM
authors.lastname: Baragi
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D048588:Benzoxazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002358:Cartilage, Articular / Q000378:metabolism; D002417:Cattle; D066298:In Vitro Techniques; D007189:Indans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007270:Injections, Intra-Articular; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D010003:Osteoarthritis / Q000188:drug therapy*; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013237:Stereoisomerism
chemical_list: C571182:4-methyl-1-((5-((3-oxo-3,4-dihydro-2H-benzo(1,4)oxazin-6-ylmethyl)carbamoyl)pyrazolo(1,5-a)pyrimidine-7-carbonyl)amino)indan-5-carboxylic acid; D018501:Antirheumatic Agents; D048588:Benzoxazines; D007189:Indans; D061965:Matrix Metalloproteinase Inhibitors