Discovery of a Potent, Selective, and Orally Active Human Epidermal Growth Factor Receptor-2 Sheddase Inhibitor for the Treatment of Cancer†

Wenqing Yao,* Jincong Zhuo, David M. Burns, Meizhong Xu, Colin Zhang, Yun-Long Li, Ding-Quan Qian, Chunhong He, Lingkai Weng, Eric Shi, Qiyan Lin, Costas Agrios, Timothy C. Burn, Eian Caulder, Maryanne B. Covington, Jordan S. Fridman, Steven Friedman, Kamna Katiyar, Gregory Hollis, Yanlong Li, Changnian Liu, Xiangdong Liu, Cindy A. Marando, Robert Newton, Max Pan, Peggy Scherle, Nancy Taylor, Kris Vaddi, Zelda R. Wasserman, Richard Wynn, Swamy Yeleswaram, Ravi Jalluri, Michael Bower, Bing-Bing Zhou, and Brian Metcalf
Incyte Corporation, Experimental Station, Wilmington, Delaware 19880
J. Med. Chem., 2007, 50 (4), pp 603–606
DOI: 10.1021/jm061344o
Publication Date (Web): January 26, 2007
Copyright © 2007 American Chemical Society
†

 Dedicated to Professor Ralph F. Hirschmann on the occasion of his 85th birthday.

,
*

 To whom correspondence should be addressed. Tel.:  302-498-6707. Fax:  302-425-2704. E-mail:  wyao@incyte.com.

Abstract

Abstract Image

The design, synthesis, evaluation, and identification of a novel class of (6S,7S)-N-hydroxy-6-carboxamide-5-azaspiro[2.5]octane-7-carboxamides as the first potent and selective inhibitors of human epidermal growth factor receptor-2 (HER-2) sheddase is described. Several compounds were identified that possess excellent pharmacodynamic and pharmacokinetic properties and were shown to decrease tumor size, cleaved HER-2 extracellular domain plasma levels, and potentiate the effects of the humanized anti-HER-2 monoclonal antibody (trastuzumab) in vivo in a HER-2 overexpressing cancer murine xenograft model.

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History

  • Published In Issue February 22, 2007
  • Received November 20, 2006

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