N-(2-alkylaminoethyl)-4-(1,2,4-oxadiazol-5-yl)piperazine-1-carboxamides as highly potent smoothened antagonists |
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Authors: | Muraglia Ester Ontoria Jesus M Branca Danila Dessole Gabriella Bresciani Alberto Fonsi Massimiliano Giuliano Claudio Llauger Bufi Laura Monteagudo Edith Palumbi Maria Cecilia Torrisi Caterina Rowley Michael Steinkühler Christian Jones Philip |
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Institution: | IRBM, Merck Research Laboratories Rome, Via Pontina km 30,600, Pomezia, 00040 Rome, Italy. |
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Abstract: | 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. |
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Keywords: | Hedgehog pathway Smoothened antagonist Hedgehog inhibitor |
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