Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part II. Identification of the 1,3,8-triazaspiro[4,5]decan-4-one privileged structure that engenders PLD2 selectivity

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:19

Article

Lavieri, Robert¹  Scott, Sarah A.¹  Lewis, Jana A.¹  Selvy, Paige E.¹  Armstrong, Michelle D.¹  Brown, H. Alex^1,2,4  Lindsley, Craig W.^1,2,3,4 

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

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

[3] Vanderbilt Univ, Vanderbilt Inst Chem Biol, Vanderbilt Program Drug Discovery, Nashville, TN 37232 USA

[4] Vanderbilt Univ, Med Ctr, Vanderbilt Inst Chem Biol, Nashville, TN 37232 USA

关键词: PLD;    Phospholipase;    Cancer;    Privileged structure;   

DOI  :  10.1016/j.bmcl.2009.02.125

来源: Elsevier

【 摘 要 】

This Letter describes the synthesis and structure-activity relationships (SAR) of isoform-selective PLD inhibitors. By virtue of the installation of a 1,3,8-triazaspiro[4,5]decan-4-one privileged structure, PLD inhibitors with nanomolar potency and an unprecedented 40-fold selectivity for PLD2 over PLD1 were developed. Interestingly, SAR for this diverged from our earlier efforts, and dual PLD1/2 inhibitors were also discovered within this series. (c) 2009 Elsevier Ltd. All rights reserved.

【 授权许可】

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