| Literature DB >> 25415648 |
Timothy B Durham1, Valentine J Klimkowski, Christopher J Rito, Jothirajah Marimuthu, James L Toth, Chin Liu, Jim D Durbin, Stephanie L Stout, Lisa Adams, Craig Swearingen, Chaohua Lin, Mark G Chambers, Kannan Thirunavukkarasu, Michael R Wiley.
Abstract
A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are zinc metalloproteases commonly referred to as aggrecanase-1 and aggrecanase-2, respectively. These enzymes are involved in the degradation of aggrecan, a key component of cartilage. Inhibitors of these enzymes could be potential osteoarthritis (OA) therapies. A series of hydantoin inhibitors of ADAMTS-4 and ADAMTS-5 were identified from a screening campaign and optimized through structure-based drug design to give hydantoin 13. Hydantoin 13 had excellent selectivity over other zinc metalloproteases such as TACE, MMP2, MMP3, MMP13, and MMP14. The compound also produced efficacy in both a chemically induced and surgical model of OA in rats.Entities:
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Year: 2014 PMID： 25415648 DOI： 10.1021/jm501522n
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446