- Discovery of Potent and Selective Inhibitors for ADAMTS-4 through DNA-Encoded Library Technology (ELT)
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The aggrecan degrading metalloprotease ADAMTS-4 has been identified as a novel therapeutic target for osteoarthritis. Here, we use DNA-encoded Library Technology (ELT) to identify novel ADAMTS-4 inhibitors from a DNA-encoded triazine library by affinity selection. Structure-activity relationship studies based on the selection information led to the identification of potent and highly selective inhibitors. For example, 4-(((4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-6-(((4-methylpiperazin-1-yl)methyl)amino)-1,3,5-triazin-2-yl)amino)methyl)-N-ethyl-N-(m-tolyl)benzamide has IC50 of 10 nM against ADAMTS-4, with >1000-fold selectivity over ADAMT-5, MMP-13, TACE, and ADAMTS-13. These inhibitors have no obvious zinc ligand functionality.
- Ding, Yun,O'Keefe, Heather,DeLorey, Jennifer L.,Israel, David I.,Messer, Jeffrey A.,Chiu, Cynthia H.,Skinner, Steven R.,Matico, Rosalie E.,Murray-Thompson, Monique F.,Li, Fan,Clark, Matthew A.,Cuozzo, John W.,Arico-Muendel, Christopher,Morgan, Barry A.
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p. 888 - 893
(2015/08/24)
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- 2,4-DIAMINO-1,3,5-TRIAZINE AND 4, 6-DIAMINO-PYRIMIDINE DERIVATIVES AND THEIR USE AS AGGRECANASE INHIBITORS
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The invention is directed to compounds of formula (I): that modulate, e.g., inhibit, aggrecanase proteolytic activity, which is implicated in joint diseases including osteoarthritis, joint injury, reactive arthritis, acute pyrophosphate arthritis, psoriatic arthritis, and rheumatoid arthritis. The current invention also relates to processes for making the compounds of the invention and to pharmaceutical compositions containing these compounds. The present invention further provides methods of treating diseases associated with aggrecanase activity, e.g., osteoarthritis and other joint diseases, using the compounds of the invention.
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Page/Page column 96
(2010/08/08)
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