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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.

By Ontoria, Jesus M.; Bufi, Laura Llauger; Torrisi, Caterina; Bresciani, Alberto; Giomini, Claudia; Rowley, Michael; Serafini, Sergio; Bin, Hu; Hao, Wu; Steinkuehler, Christian; et al
From Bioorganic & Medicinal Chemistry Letters (2011), 21(18), 5274-5282. Language: English, Database: CAPLUS, DOI:10.1016/j.bmcl.2011.07.031

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 no. 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 compds. displaying low serum shift, clean off-targets profile, and moderate clearance in both rats and dogs. These compds. are valuable tools with which to probe the biol. of the Hh-pathway.

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