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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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2010 Sep 23; Vol. 53 (18), pp. 6706-19. - Publication Year :
- 2010
-
Abstract
- 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.
- Subjects :
- Allosteric Regulation
Animals
Antineoplastic Agents pharmacokinetics
Antineoplastic Agents pharmacology
Apoptosis drug effects
Blood Proteins metabolism
Cell Line
Cell Line, Tumor
Cell Proliferation drug effects
Drug Design
Drug Screening Assays, Antitumor
Humans
Isoenzymes antagonists & inhibitors
Male
Microsomes, Liver metabolism
Naphthalenes pharmacokinetics
Naphthalenes pharmacology
Protein Binding
Rats
Rats, Sprague-Dawley
Spiro Compounds pharmacokinetics
Spiro Compounds pharmacology
Stereoisomerism
Structure-Activity Relationship
Antineoplastic Agents chemical synthesis
Naphthalenes chemical synthesis
Phospholipase D antagonists & inhibitors
Spiro Compounds chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 53
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20735042
- Full Text :
- https://doi.org/10.1021/jm100814g