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Bioorg Med Chem Lett. 2008 Jan 1;18(1):159-63. Epub 2007 Nov 4.

Design and identification of selective HER-2 sheddase inhibitors via P1' manipulation and unconventional P2' perturbations to induce a molecular metamorphosis.

Author information

1
Incyte Corporation, Department of Medicinal Chemistry, Wilmington, DE 19880, USA. wyao@incyte.com

Abstract

In an effort to obtain a MMP selective and potent inhibitor of HER-2 sheddase (ADAM-10), the P1' group of a novel class of (6S,7S)-7-[(hydroxyamino)carbonyl]-6-carboxamide-5-azaspiro[2.5]octane-5-carboxylates was attenuated and the structure-activity relationships (SAR) will be discussed. In addition, it was discovered that unconventional perturbation of the P2' moiety could confer MMP selectivity, which was hypothesized to be a manifestation of the P2' group effecting global conformational changes.

PMID:
18036818
DOI:
10.1016/j.bmcl.2007.10.108
[Indexed for MEDLINE]

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