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

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• 作者：Matthew C. O鈥橰eilly ; Sarah A. Scott ; Kyle A. Brown ; Thomas H. Oguin ; III ; Paul G. Thomas ; J. Scott Daniels ; Ryan Morrison ; H. Alex Brown ; Craig W. Lindsley
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：March 28, 2013
• 年：2013
• 卷：56
• 期：6
• 页码：2695-2699
• 全文大小：309K
• 年卷期：v.56,no.6(March 28, 2013)
• ISSN：1520-4804

文摘

An iterative parallel synthesis effort identified a PLD2 selective inhibitor, ML298 (PLD1 IC₅₀ > 20鈥?00 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.