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

By Muraglia, Ester; Ontoria, Jesus M.; Branca, Danila; Dessole, Gabriella; Bresciani, Alberto; Fonsi, Massimiliano; Giuliano, Claudio; Llauger Bufi, Laura; Monteagudo, Edith; Palumbi, Maria Cecilia; et al
From Bioorganic & Medicinal Chemistry Letters (2011), 21(18), 5283-5288. Language: English, Database: CAPLUS, DOI:10.1016/j.bmcl.2011.07.030

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 compds. in in vivo studies.

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