N-(2-alkylaminoethyl)-4-(1,2,4-oxadiazol-5-yl)piperazine-1-carboxamides as highly potent smoothened antagonists

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• 作者：Ester Muraglia^a ; Jesus M. Ontoria^a ; Danila Branca^a ; Gabriella Dessole^a ; Alberto Bresciani^a ; Massimiliano Fonsi^a ; Claudio Giuliano^a ; Laura Llauger Bufi^a ; Edith Monteagudo^a ; Maria Cecilia Palumbi^a ; Caterina Torrisi^a ; Michael Rowley^a ; 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：5283-5288
• 全文大小：1026 K

文摘

Smoothened (Smo) antagonists are emerging as new therapies for the treatment of neoplasias with aberrantly reactivated hedgehog (Hh) signaling pathway. A novel series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as smoothened antagonists was recently described, herein the series has been further optimized through the incorporation of a basic amine into the urea. This development resulted in identification of some exceptionally potent smoothened antagonists with low serum shifts, however, reductive ring opening on the 1,2,4-oxadiazole in rats limits the applicability of these compounds in in vivo studies.