Identification of a series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as potent smoothened antagonist hedgehog pathway inhibitors

详细信息    查看全文

• 作者：Jesus M. Ontoria^a ; Laura Llauger Bufi^a ; Caterina Torrisi^a ; Alberto Bresciani^a ; Claudia Giomini^a ; Michael Rowley^a ; Sergio Serafini^a ; Hu Bin^b ; Wu Hao^b ; Christian Steinkü ; hler^a ; Philip Jones^a ; ^{philip_jones@dfci.harvard.edu"" rel=""nofollow}
• 关键词：Hedgehog pathway ; Smoothened antagonist ; Hedgehog inhibitor
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2011
• 出版时间：15 September 2011
• 年：2011
• 卷：21
• 期：18
• 页码：5274-5282
• 全文大小：2207 K

文摘

The Hedgehog (Hh-) signalling pathway is a key developmental pathway and there is a growing body of evidence showing that this pathway is aberrantly reactivated in a number of human tumors. Novel agents capable of inhibiting this pathway are sought, and an entirely novel series of smoothened (Smo) antagonists capable of inhibiting the pathway have been identified through uHTS screening. Extensive exploration of the scaffold identified the key functionalities necessary for potency, enabling potent nanomolar Smo antagonists like 91 and 94 to be developed. Optimization resulted in the most advanced compounds displaying low serum shift, clean off-targets profile, and moderate clearance in both rats and dogs. These compounds are valuable tools with which to probe the biology of the Hh-pathway.