Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3K¦Â inhibitors
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- 作者：Victor Certal ; Frank Halley ; Angela Virone-Oddos ; Fabienne Thompson ; Bruno Filoche-Romm¨¦ ; Youssef El-Ahmad ; Jean-Christophe Carry ; C¨¦cile Delorme ; Andreas Karlsson ; Pierre-Yves Abecassis ; Loic Vincent ; H¨¦l¨¨ne Bonnevaux ; Jean-Paul Nicolas ; Renaud Morales ; Nadine Michot ; Isabelle Vade ; Audrey Louboutin ; S¨¦bastien Perron ; Gilles Doerflinger ; Bernadette Tric ; et al.
- 关键词：Pyrimidone anilide ; Kinase inhibitor ; PI3K¦Â ; pAkt ; PTEN
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：15 October, 2012
- 年：2012
- 卷：22
- 期：20
- 页码：6381-6384
- 全文大小：425 K
文摘
From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3K¦Â isoform. The structure of compound 1 in PI3K¦Ã was solved revealing a binding mode in agreement with the SAR observed on PI3K¦Â. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52 % bioavailability in mice and target engagement in an acute PK/PD study.