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1-Amino-4-benzylphthalazines as novel, orally bioavailable Smoothened antagonists with anti-tumor activity

Miller-Moslin, Karen and Peukert, Stefan and Mcewan, Michael and Karki, Rajesh and Llamas, Luis and Yusuff, Naeem and Dai, Miao and Perez, Lawrence and Michael, Walter and Sheng, Tao and Williams, Juliet and Dorsch, Marion and Bourret, Aaron and Ramamurthy, Arun and Yuan, Jing and Guo, Ribo and Matsumoto, Melissa and Vattay, Anthony and Maniara, Wieslawa and Amaral, Adam and Kelleher Iii, Joseph (2009) 1-Amino-4-benzylphthalazines as novel, orally bioavailable Smoothened antagonists with anti-tumor activity. Journal of Medicinal Chemistry, 52 (13). pp. 3954-3968.

Abstract

Abnormal activation of the Hh pathway has been linked to sevral types of human cancers, and the development of small-molecule inhibitors of this pathway represents a promising route towards novel anti-cancer therapeutics. A cell-base 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 analogs 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 offered tumor regression in a genetic mouse model of medulloblastoma.

Item Type: Article
Keywords: hedgehog inhibitor, Smoothened
Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/3082

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