-
David M Burns,
Yun-Long Li,
Eric Shi,
Chunhong He,
Meizhong Xu,
Jincong Zhuo,
Colin Zhang,
Ding-Quan Qian,
Yanlong Li,
Richard Wynn,
Maryanne B Covington,
Kamna Katiyar,
Cindy A Marando,
Jordan S Fridman,
Peggy Scherle,
Steve Friedman,
Brian Metcalf,
Wenqing Yao
[show abstract]
[hide abstract]
ABSTRACT: A serendipitous discovery that the metalloprotease binding profile of a novel class of 2-carboxamide-3-hydroxamic acid piperidines could be significantly attenuated by the modification of the unexplored P1 substituent enabled the design and synthesis of a novel 2-carboxamide-1-hydroxamic acid cyclohexyl scaffold core that exhibited excellent HER-2 potency and unprecedented MMP-selectivity that we believe would not have been possible via conventional P1' perturbations.
Bioorganic & medicinal chemistry letters 06/2009; 19(13):3525-30. · 2.65 Impact Factor
-
Wenqing Yao,
Jincong Zhuo, David M Burns,
Yun-Long Li,
Ding-Quan Qian,
Colin Zhang,
Chunhong He,
Meizhong Xu,
Eric Shi,
Yanlong Li, [......],
Max Pan,
Jordan S Fridman,
Peggy Scherle,
Zelda R Wasserman,
Gregory Hollis,
Kris Vaddi,
Swamy Yeleswaram,
Robert Newton,
Steve Friedman,
Brian Metcalf
[show abstract]
[hide abstract]
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.
Bioorganic & medicinal chemistry letters 02/2008; 18(1):159-63. · 2.65 Impact Factor
-
David M Burns,
Chunhong He,
Yanlong Li,
Peggy Scherle,
Xiangdong Liu,
Cindy A Marando,
Mayanne B Covington,
Gengjie Yang,
Max Pan,
Sharon Turner,
Jordan S Fridman,
Gregory Hollis,
Kris Vaddi,
Swamy Yeleswaram,
Robert Newton,
Steve Friedman,
Brian Metcalf,
Wenqing Yao
[show abstract]
[hide abstract]
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.
Bioorganic & medicinal chemistry letters 02/2008; 18(2):560-4. · 2.65 Impact Factor
-
Wenqing Yao,
Jincong Zhuo, David M Burns,
Meizhong Xu,
Colin Zhang,
Yun-Long Li,
Ding-Quan Qian,
Chunhong He,
Lingkai Weng,
Eric Shi, [......],
Peggy Scherle,
Nancy Taylor,
Kris Vaddi,
Zelda R Wasserman,
Richard Wynn,
Swamy Yeleswaram,
Ravi Jalluri,
Michael Bower,
Bing-Bing Zhou,
Brian Metcalf
[show abstract]
[hide abstract]
ABSTRACT: 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.
Journal of Medicinal Chemistry 03/2007; 50(4):603-6. · 5.25 Impact Factor
