1-amino-4-benzylphthalazines as orally bioavailable smoothened antagonists with antitumor activity

  • J Med Chem. 2009 Jul 9;52(13):3954-68. doi: 10.1021/jm900309j.
Karen Miller-Moslin  1 ,  Stefan Peukert ,  Rishi K Jain ,  Michael A McEwan ,  Rajesh Karki ,  Luis Llamas ,  Naeem Yusuff ,  Feng He ,  Yanhong Li ,  Yingchuan Sun ,  Miao Dai ,  Lawrence Perez ,  Walter Michael ,  Tao Sheng ,  Huangshu Lei ,  Rui Zhang ,  Juliet Williams ,  Aaron Bourret ,  Arun Ramamurthy ,  Jing Yuan ,  Ribo Guo ,  Melissa Matsumoto ,  Anthony Vattay ,  Wieslawa Maniara ,  Adam Amaral ,  Marion Dorsch ,  Joseph F Kelleher 3rd
Affiliations
  • 1. Department of Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 01239, USA. [email protected]
PMID: 19469545 DOI: 10.1021/jm900309j
Abstract

Abnormal activation of the Hedgehog (Hh) signaling pathway has been linked to several types of human cancers, and the development of small-molecule inhibitors of this pathway represents a promising route toward novel Anticancer therapeutics. A cell-based screen performed in our laboratories identified a new class of Hh pathway inhibitors, 1-amino-4-benzylphthalazines, that act via antagonism of the Smoothened receptor. A variety of analogues were synthesized and their structure-activity relationships determined. This optimization resulted in the discovery of high affinity Smoothened antagonists, one of which was further profiled in vivo. This compound displayed a good pharmacokinetic profile and also afforded tumor regression in a genetic mouse model of Medulloblastoma.

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