Discovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective PI3K尾 Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers

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• 作者：Victor Certal ; Frank Halley ; Angela Virone-Oddos ; C茅cile Delorme ; Andreas Karlsson ; Alexey Rak ; Fabienne Thompson ; Bruno Filoche-Romm茅 ; Youssef El-Ahmad ; Jean-Christophe Carry ; Pierre-Yves Abecassis ; Pascale Lejeune ; Loic Vincent ; H茅l猫ne Bonnevaux ; Jean-Paul Nicolas ; Thomas Bertrand ; Jean-Pierre Marquette ; Nadine Michot ; Tsiala Benard ; Peter Below ; Isabelle Vade ; Fabienne Chatreaux ; Gilles Lebourg ; Fabienne Pilorge ; Odile Angouillant-Boniface ; Audrey Louboutin ; Christoph Lengauer ; Laurent Schio
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 24, 2012
• 年：2012
• 卷：55
• 期：10
• 页码：4788-4805
• 全文大小：642K
• 年卷期：v.55,no.10(May 24, 2012)
• ISSN：1520-4804

文摘

Most of the phosphoinositide-3 kinase (PI3K) kinase inhibitors currently in clinical trials for cancer treatment exhibit pan PI3K isoform profiles. Single PI3K isoforms differentially control tumorigenesis, and PI3K尾 has emerged as the isoform involved in the tumorigenicity of PTEN-deficient tumors. Herein we describe the discovery and optimization of a new series of benzimidazole- and benzoxazole-pyrimidones as small molecular mass PI3K尾-selective inhibitors. Starting with compound 5 obtained from a one-pot reaction via a novel intermediate 1, medicinal chemistry optimization led to the discovery of compound 8, which showed a significant activity and selectivity for PI3K尾 and adequate in vitro pharmacokinetic properties. The X-ray costructure of compound 8 in PI3K未 showed key interactions and structural features supporting the observed PI3K尾 isoform selectivity. Compound 8 achieved sustained target modulation and tumor growth delay at well tolerated doses when administered orally to SCID mice implanted with PTEN-deficient human tumor xenografts.