Author/Authors :
Mark C. Noe، نويسنده , , Vijayalakshmi Natarajan، نويسنده , , Sheri L. Snow، نويسنده , , Lilli A. Wolf-Gouveia، نويسنده , , Peter G. Mitchell، نويسنده , , Lori Lopresti-Morrow، نويسنده , , Lisa M. Reeves، نويسنده , , Sue A. Yocum، نويسنده , , Ivan Otterness، نويسنده , , Marcia A. Bliven، نويسنده , , Thomas J. Carty، نويسنده , , John T. Barberia، نويسنده , , Francis J. Sweeney، نويسنده , , Jennifer L. Liras، نويسنده , , Marcie Vaughn، نويسنده ,
Abstract :
A series of 3-hydroxy-3-methylpipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was designed based on the observation of increased aggrecanase activity with substitution at the 3-position of the piperidine ring. Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group that binds in the S1′ pocket. These compounds also possess markedly improved bioavailability and lower metabolic clearance compared to analogous 3,3-dimethyl-5-hydroxypipecolic hydroxamates. These improvements are attributed to lowered lipophilicity proximal to the metabolically labile hydroxamic acid. Synthesis, structure activity relationships, and in vivo efficacy data are described.
