Conversion of an MMP-potent scaffold to an MMP-selective HER-2 sheddase inhibitor via scaffold hybridization and subtle P1' permutations.
Basic Information
ID: ALA1140810
Journal: Bioorg Med Chem Lett
Title: Conversion of an MMP-potent scaffold to an MMP-selective HER-2 sheddase inhibitor via scaffold hybridization and subtle P1' permutations.
Authors: Burns DM, He C, Li Y, Scherle P, Liu X, Marando CA, Covington MB, Yang G, Pan M, Turner S, Fridman JS, Hollis G, Vaddi K, Yeleswaram S, Newton R, Friedman S, Metcalf B, Yao W.
Abstract: A series of beta-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 S(1)(') binding pocket of the active sites within the metalloprotease family. In addition, it was discovered that the introduction of polarity to the P(1) and P(1)(') groups reduced the projected human clearance.
CiteXplore: 18068976
DOI: 10.1016/j.bmcl.2007.11.086
Patent ID: ┄