Discovery of novel, highly potent, and selective quinazoline-2-carboxamide-based matrix metalloproteinase (MMP)-13 inhibitors without a zinc binding group using a structure-based design approach.

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.
AuthorsHiroshi Nara, Kenjiro Sato, Takako Naito, Hideyuki Mototani, Hideyuki Oki, Yoshio Yamamoto, Haruhiko Kuno, Takashi Santou, Naoyuki Kanzaki, Jun Terauchi, Osamu Uchikawa, Masakuni Kori
JournalJournal of medicinal chemistry (J Med Chem) Vol. 57 Issue 21 Pg. 8886-902 (Nov 13 2014) ISSN: 1520-4804 [Electronic] United States
PMID25264600 (Publication Type: Journal Article)
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
  • 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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