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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Nara H,Sato K,Naito T,Mototani H,Oki H,Yamamoto Y,Kuno H,Santou T,Kanzaki N,Terauchi J,Uchikawa O,Kori Mdoi
10.1021/jm500981ksubject
Has Abstractpub_date
2014-11-13 00:00:00pages
8886-902issue
21eissn
0022-2623issn
1520-4804journal_volume
57pub_type
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