Author/Authors :
David M. Burns، نويسنده , , Chunhong He، نويسنده , , Yanlong Li، نويسنده , , Peggy Scherle، نويسنده , , Xiangdong Liu، نويسنده , , Cindy A. Marando، نويسنده , , Mayanne B. Covington، نويسنده , , Gengjie Yang، نويسنده , , Max Pan، نويسنده , , Sharon Turner، نويسنده , , Jordan S. Fridman، نويسنده , , Gregory Hollis، نويسنده , , Kris Vaddi، نويسنده , , Swamy Yeleswaram، نويسنده , , Robert Newton، نويسنده , , Steve Friedman، نويسنده , , Brian Metcalf، نويسنده , , Wenqing Yao، نويسنده ,
Abstract :
A series of β-sulfonamide piperidine hydroxamates were prepared and shown to be potent inhibitors of the human epidermal growth factor receptor-2 (HER-2) sheddase with excellent selectivity against MMP-1, −2, −3, and −9. This was achieved by exploiting subtle differences within the otherwise highly conserved binding pocket of the active sites within the metalloprotease family. In addition, it was discovered that the introduction of polarity to the P1 and groups reduced the projected human clearance.
Keywords :
HER-2 sheddase , ADAM-10 , Beta-sulfonamide piperidine hydroxamates , metalloprotease , MMP , P1? substituent , Projected clearnace , Scaffold hybridization
