title: Conversion of an MMP-potent scaffold to an MMP-selective HER-2 sheddase inhibitor via scaffold hybridization and subtle P1' permutations.
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.
authors: Department of Medicinal Chemistry, Incyte Corporation, Wilmington, DE 19880, USA. dburns@incyte.com
authors: David M
authors: DM
authors: Burns
authors: Chunhong
authors: C
authors: He
authors: Yanlong
authors: Y
authors: Li
authors: Peggy
authors: P
authors: Scherle
authors: Xiangdong
authors: X
authors: Liu
authors: Cindy A
authors: CA
authors: Marando
authors: Mayanne B
authors: MB
authors: Covington
authors: Gengjie
authors: G
authors: Yang
authors: Max
authors: M
authors: Pan
authors: Sharon
authors: S
authors: Turner
authors: Jordan S
authors: JS
authors: Fridman
authors: Gregory
authors: G
authors: Hollis
authors: Kris
authors: K
authors: Vaddi
authors: Swamy
authors: S
authors: Yeleswaram
authors: Robert
authors: R
authors: Newton
authors: Steve
authors: S
authors: Friedman
authors: Brian
authors: B
authors: Metcalf
authors: Wenqing
authors: W
authors: Yao
mesh_terms: D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000737:chemistry / Q000378:metabolism*; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D020782:Matrix Metalloproteinases; D010880:Piperidines; D018719:Erb-b2 Receptor Tyrosine Kinases