Design, synthesis, and biological evaluation of halogenated N-(2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)ethyl)benzamides: discovery of an isoform-selective small molecule phospholipase D2 inhibitor.

Lavieri RR, Scott SA, Selvy PE, Kim K, Jadhav S, Morrison RD, Daniels JS, Brown HA, Lindsley CW
J Med Chem. 2010 53 (18): 6706-19

PMID: 20735042 · PMCID: PMC3179181 · DOI:10.1021/jm100814g

Phospholipase D (PLD) catalyzes the conversion of phosphatidylcholine to the lipid second messenger phosphatidic acid. Two mammalian isoforms of PLD have been identified, PLD1 and PLD2, which share 53% sequence identity and are subject to different regulatory mechanisms. Inhibition of PLD enzymatic activity leads to increased cancer cell apoptosis, decreased cancer cell invasion, and decreased metastasis of cancer cells; therefore, the development of isoform-specific, PLD inhibitors is a novel approach for the treatment of cancer. Previously, we developed potent dual PLD1/PLD2, PLD1-specific (>1700-fold selective), and moderately PLD2-preferring (>10-fold preferring) inhibitors. Here, we describe a matrix library strategy that afforded the most potent (PLD2 IC(50) = 20 nM) and selective (75-fold selective versus PLD1) PLD2 inhibitor to date, N-(2-(1-(3-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl)ethyl)-2-naphthamide (22a), with an acceptable DMPK profile. Thus, these new isoform-selective PLD inhibitors will enable researchers to dissect the signaling roles and therapeutic potential of individual PLD isoforms to an unprecedented degree.

MeSH Terms (22)

Allosteric Regulation Animals Antineoplastic Agents Apoptosis Blood Proteins Cell Line Cell Line, Tumor Cell Proliferation Drug Design Drug Screening Assays, Antitumor Humans Isoenzymes Male Microsomes, Liver Naphthalenes Phospholipase D Protein Binding Rats Rats, Sprague-Dawley Spiro Compounds Stereoisomerism Structure-Activity Relationship

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