title: Characterization of selective exosite-binding inhibitors of matrix metalloproteinase 13 that prevent articular cartilage degradation in vitro.
abstract: Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis and therefore represents a target for drug development. As a result of high-throughput screening and structure-activity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding constants in the low micromolar range. Crystallographic analyses revealed two binding modes for compound 2 in the MMP-13 S1' subsite and in an S1/S2* subsite. Type II collagen- and cartilage-protective effects exhibited by compounds 1, 2, and 3 suggested that these compounds might be efficacious in future in vivo studies. Finally, these compounds were also highly selective when tested against a panel of 30 proteases, which, in combination with a good CYP inhibition profile, suggested low off-target toxicity and drug-drug interactions in humans.
authors.affiliation: Lead Identification Division, Translational Research Institute, ‡Department of Molecular Therapeutics, and §Department of Chemistry, Scripps Florida, The Scripps Research Institute , Jupiter, Florida 33458, United States.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Spicer
authors.forename: Jianwen
authors.initials: J
authors.lastname: Jiang
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Taylor
authors.forename: Jun Yong
authors.initials: JY
authors.lastname: Choi
authors.forename: P John
authors.initials: PJ
authors.lastname: Hart
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
authors.forename: Gregg B
authors.initials: GB
authors.lastname: Fields
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hodder
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Minond
mesh_terms: D000818:Animals; D001665:Binding Sites; D002356:Cartilage / Q000378:metabolism; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003094:Collagen / Q000737:chemistry; D017364:Collagenases / Q000737:chemistry; D018360:Crystallography, X-Ray / Q000379:methods; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D007700:Kinetics; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry*; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry*; D051379:Mice; D008861:Microsomes / Q000187:drug effects; D008968:Molecular Conformation; D010003:Osteoarthritis / Q000503:physiopathology; D011485:Protein Binding; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D003094:Collagen; D003577:Cytochrome P-450 Enzyme System; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13