PKI-179: An orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor

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• 作者：Aranapakam M. Venkatesan ; Zecheng Chen ; Osvaldo Dos Santos ; Christoph Dehnhardt ; Efren Delos Santos ; Semiramis Ayral-Kaloustian ; Robert Mallon ; Irwin Holl ; er ; Larry Feldberg ; Judy Lucas ; Ker Yu ; Inder
• 关键词：Phosphatidylinositol-3-kinase (PI3K) ; PI3K/Akt/mTOR pathway ; Dual PI3-kinase/mTOR inhibitors ; PKI-587 ; PKI-179
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2010
• 出版时间：1 October 2010
• 年：2010
• 卷：20
• 期：19
• 页码：5869-5873
• 全文大小：1327 K

文摘

A series of mono-morpholino 1,3,5-triazine derivatives (8a–8q) bearing a 3-oxa-8-azabicyclo[3.2.1]octane were prepared and evaluated for PI3-kinase/mTOR activity. Replacement of one of the bis-morpholines in lead compound 1 (PKI-587) with 3-oxa-8-azabicyclo[3.2.1]octane and reduction of the molecular weight yielded 8m (PKI-179), an orally efficacious dual PI3-kinase/mTOR inhibitor. The in vitro activity, in vivo efficacy, and PK properties of 8m are discussed.