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Bioorg Med Chem Lett. 2010 Jun 15;20(12):3526-9. doi: 10.1016/j.bmcl.2010.04.139. Epub 2010 May 17.

5-ureidobenzofuranone indoles as potent and efficacious inhibitors of PI3 kinase-alpha and mTOR for the treatment of breast cancer.

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Discovery Medicinal Chemistry, Wyeth Research, Pearl River, NY 10965, USA.


A series of 5-ureidobenzofuran-3-one indoles as potent inhibitors of PI3Kalpha and mTOR has been developed. The best potency in cells was obtained when the urea group was extended to a 4-[2-(dimethylamino)ethyl]methylamino amidophenyl group. A 7-fluoro group on the indole ring also enhanced cellular potency. Compound 18i, incorporating the optimal functional groups, showed high potency in cellular lines and was further studied in vivo. It was able to inhibit the biomarker phosphorylation for 8h when dosed at 25 mg/kg iv. In the MDA-MB-361 breast cancer model, it shrank the tumor size remarkably when dosed at 25 mg/kg iv on days 1, 5, and 9.

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