Development of Dual PLD1/2 and PLD2 Selective Inhibitors from a Common 1,3,8-Triazaspiro[4.5]decane Core: Discovery of ML298 and ML299 That Decrease Invasive Migration in U87-MG Glioblastoma Cells

被引：54

作者：

O'Reilly, Matthew C. ^{[3
]}

Scott, Sarah A. ^{[1
,4
]}

Brown, Kyle A. ^{[1
,2
,3
]}

Oguin, Thomas H., III ^{[5
]}

Thomas, Paul G. ^{[5
]}

Daniels, J. Scott ^{[1
,2
,4
]}

Morrison, Ryan ^{[1
,2
,4
]}

Brown, H. Alex ^{[1
,3
]}

Lindsley, Craig W. ^{[1
,2
,3
,4
]}

机构：

[1] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Dept Chem, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Vanderbilt Specialized Chem Accelerated Probe Dev, Nashville, TN 37232 USA

[5] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 06期

关键词：

PHOSPHOLIPASE D2; DESIGN; HALOPEMIDE;

D O I：

10.1021/jm301782e

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

An iterative parallel synthesis effort identified a PLD2 selective inhibitor, ML298 (PLD1 IC50 > 20 000 nM, PLD2 IC50 = 355 nM) and a dual PLD1/2 inhibitor, ML299 (PLD1 IC50 = 6 nM, PLD2 IC50 = 20 nM). SAR studies revealed that a small structural change (incorporation of a methyl group) increased PLD1 activity within this classically PLD2-preferring core and that the effect was enantiospecific. Both probes decreased invasive migration in U87-MG glioblastoma cells.

引用

页码：2695 / 2699

页数：5

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