Discovery of phosphoinositide 3-kinases (PI3K) p110¦Â isoform inhibitor 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H-pyrimidin-2-one, an effective antithrombotic agent without associated bleeding and insulin resistance
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- 作者：Fabrizio Giordanetto ; Andreas W?llberg ; Saswati Ghosal ; Tommy Iliefski ; Johan Cassel ; Zhong-Qing Yuan ; Henrik von Wachenfeldt ; S?ren M. Andersen ; Tord Inghardt ; Anders Tunek ; Sven Nyl ; er
- 关键词：Fragment-based ; Phosphoinositide 3-kinase ; PI3K ; p110¦Â ; Inhibitor ; Thromboembolism ; Anti-thrombotic agent ; Insulin resistance
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：1 November, 2012
- 年：2012
- 卷：22
- 期：21
- 页码：6671-6676
- 全文大小：604 K
文摘
Structure-based evolution of the original fragment leads resulted in the identification of 4-[2-hydroxyethyl(1-naphthylmethyl)amino]-6-[(2S)-2-methylmorpholin-4-yl]-1H-pyrimidin-2-one, (S)-21, a potent, selective phosphoinositide 3-kinases (PI3K) p110¦Â isoform inhibitor with favourable in vivo antiplatelet effect. Despite its antiplatelet action, (S)-21 did not significantly increase bleeding time in dogs. Additionally, due to its enhanced selectivity over p110¦Á, (S)-21 did not induce any insulin resistance in rats.