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

• Published in: Journal of medicinal chemistry Vol. 53; no. 18; pp. 6706 - 6719
• Main Authors: Lavieri, Robert R, Scott, Sarah A, Selvy, Paige E, Kim, Kwangho, Jadhav, Satyawan, Morrison, Ryan D, Daniels, J. Scott, Brown, H. Alex, Lindsley, Craig W
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 23.09.2010; Amer Chemical Soc
• Subjects: Allosteric Regulation; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Blood Proteins - metabolism; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Drug Design; Drug Screening Assays, Antitumor; Humans; Isoenzymes - antagonists & inhibitors; Life Sciences & Biomedicine; Male; Microsomes, Liver - metabolism; Naphthalenes - chemical synthesis; Naphthalenes - pharmacokinetics; Naphthalenes - pharmacology; Pharmacology & Pharmacy; Phospholipase D - antagonists & inhibitors; Protein Binding; Rats; Rats, Sprague-Dawley; Science & Technology; Spiro Compounds - chemical synthesis; Spiro Compounds - pharmacokinetics; Spiro Compounds - pharmacology; Stereoisomerism; Structure-Activity Relationship; STIMULATED HUMAN NEUTROPHILS; BREAST-CANCER CELLS; OVEREXPRESSION; ACTIVATION; PROTEIN; RAS; SURVIVAL SIGNALS; PHOSPHATIDIC-ACID; D1; EXPRESSION
• ISSN: 0022-2623; 1520-4804; 1520-4804
• 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 IC50 = 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.