Author/Authors :
Mark C. Noe، نويسنده , , Vijayalakshmi Natarajan، نويسنده , , Sheri L. Snow، نويسنده , , Peter G. Mitchell، نويسنده , , Lori Lopresti-Morrow، نويسنده , , Lisa M. Reeves، نويسنده , , Sue A. Yocum، نويسنده , , Thomas J. Carty، نويسنده , , John A. Barberia، نويسنده , , Francis J. Sweeney، نويسنده , , Jennifer L. Liras، نويسنده , , Marcie Vaughn، نويسنده , , Joel R. Hardink، نويسنده , , Joel M. Hawkins، نويسنده , , Christopher Tokar، نويسنده ,
Abstract :
A series of pipecolic hydroxamate inhibitors of MMP-13 and aggrecanase was discovered based on screening known inhibitors of TNF-α converting enzyme (TACE). Potency versus aggrecanase was optimized by modification of the benzyloxyarylsulfonamide group. Incorporation of geminal alkyl substitution at the 3-position of the piperidine ring improved metabolic stability, presumably by increasing steric hindrance around the metabolically labile hydroxamic acid. This modification also resulted in dramatic improvement of aggrecanase activity with a slight reduction in selectivity versus MMP-1. Synthesis, structure activity relationships, and strategies to reduce metabolic clearance are described.
