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Synthesis and biological evaluation of biphenylsulfonamide carboxylate aggrecanase-1 inhibitors |
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| Authors: | Xiang Jason S Hu Yonghan Rush Thomas S Thomason Jennifer R Ipek Manus Sum Phaik-Eng Abrous Leila Sabatini Joshua J Georgiadis Katy Reifenberg Erica Majumdar Manas Morris Elisabeth A Tam Steve |
| Institution: | Department of Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. |
| Abstract: | Aggrecanases are recently discovered enzymes that cleave aggrecan, a key component of cartilage. Aggrecanase inhibitors may provide a unique means to halt the progression of cartilage destruction in osteoarthritis. The synthesis and evaluation of biphenylsulfonamidocarboxylic acid inhibitors of aggrecanase-1 are reported. Compound 24 demonstrated 89% inhibition of proteoglycan degradation at 10 microg/mL and has an oral bioavailability in rat of 35%. |
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