Abstract |
Matrix metalloproteinase-13 (MMP-13) has been implicated to play a key role in the pathology of osteoarthritis. On the basis of X-ray crystallography, we designed a series of potent MMP-13 selective inhibitors optimized to occupy the distinct deep S1' pocket including an adjacent branch. Among them, carboxylic acid inhibitor 21k exhibited excellent potency and selectivity for MMP-13 over other MMPs. An effort to convert compound 21k to the mono sodium salt 38 was promising in all animal species studied. Moreover, no overt toxicity was observed in a preliminary repeat dose oral toxicity study of compound 21k in rats. A single oral dose of compound 38 significantly reduced degradation products (CTX-II) released from articular cartilage into the joint cavity in a rat MIA model in vivo. In this article, we report the discovery of highly potent, selective, and orally bioavailable MMP-13 inhibitors as well as their detailed structure-activity data.
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Authors | Hiroshi Nara, Kenjiro Sato, Takako Naito, Hideyuki Mototani, Hideyuki Oki, Yoshio Yamamoto, Haruhiko Kuno, Takashi Santou, Naoyuki Kanzaki, Jun Terauchi, Osamu Uchikawa, Masakuni Kori |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 57
Issue 21
Pg. 8886-902
(Nov 13 2014)
ISSN: 1520-4804 [Electronic] United States |
PMID | 25264600
(Publication Type: Journal Article)
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Chemical References |
- 4-(2-((6-fluoro-2-((((3-(methyloxy)phenyl)methyl)amino)carbonyl)-4-oxo-3,4-dihydroquinazolin-5-yl)oxy)ethyl)benzoic acid
- Benzoates
- Matrix Metalloproteinase Inhibitors
- Quinazolines
- Matrix Metalloproteinase 13
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Topics |
- Animals
- Benzoates
(chemical synthesis, pharmacokinetics, pharmacology)
- Binding Sites
- Crystallography, X-Ray
- Humans
- Inhibitory Concentration 50
- Matrix Metalloproteinase 13
(drug effects)
- Matrix Metalloproteinase Inhibitors
(chemical synthesis, pharmacokinetics, pharmacology)
- Osteoarthritis
(drug therapy)
- Quinazolines
(chemical synthesis, pharmacokinetics, pharmacology)
- Rats
- Structure-Activity Relationship
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