Discovery of 3-Oxabicyclo[4.1.0]heptane, a Non-nitrogen Containing Morpholine Isostere, and Its Application in Novel Inhibitors of the PI3K-AKT-mTOR Pathway

Hobbs Heather; Bravi Gianpaolo; Campbell Ian; Convery Maire; Davies Hannah; Inglis Graham; Pal Sandeep; Peace Simon; Redmond Joanna; Summers Declan

首页> 外文期刊>Journal of Medicinal Chemistry >Discovery of 3-Oxabicyclo[4.1.0]heptane, a Non-nitrogen Containing Morpholine Isostere, and Its Application in Novel Inhibitors of the PI3K-AKT-mTOR Pathway

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Discovery of 3-Oxabicyclo[4.1.0]heptane, a Non-nitrogen Containing Morpholine Isostere, and Its Application in Novel Inhibitors of the PI3K-AKT-mTOR Pathway

机译：发现3-氧基酰亚乙二醇[4.1.0]庚烷，含有的含硫胺虫等渗，其在PI3K-AKT-MTOR途径新抑制剂中的应用

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4-(Pyrimidin-4-yl)morpholines are privileged pharmacophores for PI3K and PIKKs inhibition by virtue of the morpholine oxygen, both forming the key hydrogen bonding interaction and conveying selectivity over the broader kinome. Key to the morpholine utility as a kinase hinge binder is its ability to adopt a coplanar conformation with an adjacent aromatic core favored by the morpholine nitrogen nonbonding pair of electrons interacting with the electron deficient pyrimidine pi-system. Few selective morpholine replacements have been identified to date. Herein we describe the discovery of a potent non-nitrogen containing morpholine isostere with the ability to mimic this conformation and its application in a potent selective dual inhibitor of mTORC1 and mTORC2 (29b).

机译：4-（嘧啶-4-基）吗啉是PI3K和PIKKs借助于吗啡氧的特权药程，两者在更广泛的Kinome上形成关键的氢键相互作用和输送选择性。作为激酶铰链粘合剂作为激酶铰链粘合剂的键是其与由与电子缺乏嘧啶Pi-System相互作用的正文氮非粘合对电子有关的相邻芳族芯的共面构象的能力。已经确定了迄今为止的选择性吗啡替换。在本文中，我们描述了含有含量的含量的吗啉等甾体的能力，其能够模仿这种构象的能力及其在MTORC1和MTORC2（29b）的有效选择性双重抑制剂中的应用。

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《Journal of Medicinal Chemistry》 |2019年第15期|共13页
作者
Hobbs Heather; Bravi Gianpaolo; Campbell Ian; Convery Maire; Davies Hannah; Inglis Graham; Pal Sandeep; Peace Simon; Redmond Joanna; Summers Declan;
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GlaxoSmithKline R&

D Gunnels Wood Rd Stevenage SG1 2NY Herts England;

GlaxoSmithKline R&

D Gunnels Wood Rd Stevenage SG1 2NY Herts England;

GlaxoSmithKline R&

D Gunnels Wood Rd Stevenage SG1 2NY Herts England;

GlaxoSmithKline R&

D Gunnels Wood Rd Stevenage SG1 2NY Herts England;

GlaxoSmithKline R&

D Gunnels Wood Rd Stevenage SG1 2NY Herts England;

GlaxoSmithKline R&

D Gunnels Wood Rd Stevenage SG1 2NY Herts England;

GlaxoSmithKline R&

D Gunnels Wood Rd Stevenage SG1 2NY Herts England;

GlaxoSmithKline R&

D Gunnels Wood Rd Stevenage SG1 2NY Herts England;

GlaxoSmithKline R&

D Gunnels Wood Rd Stevenage SG1 2NY Herts England;

GlaxoSmithKline R&

D Gunnels Wood Rd Stevenage SG1 2NY Herts England;

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正文语种 eng
中图分类药学;
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1. Discovery of 3-Oxabicyclo[4.1.0]heptane, a Non-nitrogen Containing Morpholine Isostere, and Its Application in Novel Inhibitors of the PI3K-AKT-mTOR Pathway (vol 62, pg 6972, 2019) [J] . Hobbs Heather, Bravi Gianpaolo, Campbell Ian, Journal of Medicinal Chemistry . 2019,第19期

机译：发现3-氧基酰亚乙二醇[4.1.0]庚烷，含有非氮素的吗啉等甾酮，其在PI3K-AKT-MTOR途径新抑制剂中的应用（Vol 62，PG 6972，2019）
2. Erratum to:Discovery of Chrysoeriol,a PI3K-AKT-mTOR Pathway Inhibitor with Potent Antitumor Activity against Human Multiple Myeloma Cells In Vitro [J] . Yang YANG, Xiaoxi ZHOU, Min XIAO, 当代医学科学(英文) . 2020,第006期

机译：误解：发现克莱氏醇，PI3K-AKT-MTOR途径抑制剂，其具有抗体多发性骨髓瘤细胞的有效抗肿瘤活性
3. 1-Heteroaryl-6-(3,4-dichlorophenyl)-3-azabicyclo(4.1.0)heptane: further insights into a class of triple re-uptake inhibitors. [J] . Micheli F, Cavanni P, Bettati M, Bioorganic and medicinal chemistry . 2011,第11期

机译：1-杂芳基-6-（3,4-二氯苯基）-3-氮杂双环（4.1.0）庚烷：深入了解一类三重再摄取抑制剂。
4. Synthesis of inhibitors of the heptose biosynthetic pathway for the discovery of Antivirulence and Antibacterial Agents [C] . Stephane P. VINCENT International Carbohydrate Symposium . 2013

机译：肽生物合成途径抑制剂的合成抗血管和抗菌剂的发现
5. Application of organocatalysis to the synthesis of chiral morpholines, piperazines, aziridines, azetidines, beta-fluoroamines, and gamma-fluoroamines; discovery of selective phospholipase D inhibitors with optimized in vivo properties. [D] . O'Reilly, Matthew C. 2014

机译：有机催化在合成手性吗啉，哌嗪，氮丙啶，氮杂环丁烷，β-氟胺和γ-氟胺中的应用；发现具有优化体内特性的选择性磷脂酶D抑制剂。
6. Fragment based discovery of Arginine isosteres through REPLACE: towards non-ATP competitive CDK inhibitors [O] . Padmavathy Nandha Premnath, Shu Liu, Tracy Perkins, -1

机译：通过REPLACE基于片段的精氨酸等位基因发现：针对非ATP竞争性CDK抑制剂
7. Correction to Discovery of 3-Oxabicyclo4.1.0heptane, a Non-nitrogen Containing Morpholine Isostere, and Its Application in Novel Inhibitors of the PI3K-AKT-mTOR Pathway [O] . Heather Hobbs, Gianpaolo Bravi, Ian Campbell, 2019

机译：校正3-氧基双环4.1.0庚烷，一种含有的吗啉异蹄孔的校正及其在PI3K-AKT-MTOR途径的新抑制剂中的应用

Discovery of 3-Oxabicyclo[4.1.0]heptane, a Non-nitrogen Containing Morpholine Isostere, and Its Application in Novel Inhibitors of the PI3K-AKT-mTOR Pathway

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