Identification of novel, exosite-binding matrix metalloproteinase-13 inhibitor scaffolds.
Matrix metalloproteinase-13 (MMP-13) has been implicated as the protease responsible for collagen degradation in cartilage during osteoarthritis (OA). Compounds that inhibit the metalloproteinase at the Zn binding site typically lack specificity among MMP family members. Analogs of the low-micromolar lead MMP-13 inhibitor 4, discovered through high-throughput screening, were synthesized to investigate structure-activity relationships in this inhibitor series. Systematic modifications of 4 led to the discovery of MMP-13 inhibitors 20 and 24 which are more selective than 4 against other MMPs. Compound 20 is also approximately fivefold more potent as an MMP-13 inhibitor than the original HTS-derived lead compound 4.
Department of Chemistry, Scripps Florida, Jupiter, FL 33458, United States.
Joshua
J
Roth
Dmitriy
D
Minond
Etzer
E
Darout
Qin
Q
Liu
Janelle
J
Lauer
Peter
P
Hodder
Gregg B
GB
Fields
William R
WR
Roush
D001665:Binding Sites; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014498:Uracil / Q000031:analogs & derivatives / Q000737:chemistry
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D014498:Uracil; C068989:cyclopentenyluracil; D053509:Matrix Metalloproteinase 13