Author/Authors :
Robert J. Cherney، نويسنده , , Ruowei Mo، نويسنده , , Dayton T. Meyer، نويسنده , , Li Wang، نويسنده , , Wenqing Yao، نويسنده , , Zelda R. Wasserman، نويسنده , , Ruiqin Liu، نويسنده , , Maryanne B. Covington، نويسنده , , Micky D. Tortorella، نويسنده , , Elizabeth C. Arner، نويسنده , , Mingxin Qian، نويسنده , , David D. Christ، نويسنده , , James M. Trzaskos، نويسنده , , Robert C. Newton، نويسنده , , Ron L. Magolda، نويسنده , , Carl P. Decicco، نويسنده ,
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 IC50=3 nM 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.
