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ID: ALA1136683
Journal: Bioorg Med Chem Lett
Title: Potent and selective aggrecanase inhibitors containing cyclic P1 substituents.
Authors: Cherney RJ, Mo R, Meyer DT, Wang L, Yao W, Wasserman ZR, Liu RQ, Covington MB, Tortorella MD, Arner EC, Qian M, Christ DD, Trzaskos JM, Newton RC, Magolda RL, Decicco CP.
Abstract: Anti-succinate hydroxamates with cyclic P1 motifs were synthesized as aggrecanase inhibitors. The N-methanesulfonyl piperidine 23 and the N-trifluoroacetyl azetidine 26 were the most potent aggrecanase inhibitors both having an IC(50)=3nM while maintaining >100-fold selectivity over MMP-1, -2, and -9. The cyclic moieties were also capable of altering in vivo metabolism, hence delivering low clearance compounds in both rat and dog studies as shown for compound 14.
CiteXplore: 12657268