Discovery of a Highly Selective PLD2 Inhibitor (ML395): A New Probe with Improved Physiochemical Properties and Broad-Spectrum Antiviral Activity against Influenza Strains

• Published in: ChemMedChem Vol. 9; no. 12; pp. 2633 - 2637
• Main Authors: O'Reilly, Matthew C., Oguin III, Thomas H., Scott, Sarah A., Thomas, Paul G., Locuson, Charles W., Morrison, Ryan D., Daniels, J. Scott, Brown, H. Alex, Lindsley, Craig W.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01.12.2014; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Subjects: Animals; Antiviral Agents - chemistry; Antiviral Agents - pharmacokinetics; Antiviral Agents - toxicity; antivirals; Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Medicinal; Dogs; Half-Life; Humans; Imidazolidines - chemistry; Imidazolidines - pharmacokinetics; Imidazolidines - toxicity; Influenza; Influenza A Virus, H1N1 Subtype - drug effects; Influenza A Virus, H3N2 Subtype - drug effects; Influenza A Virus, H5N1 Subtype - drug effects; Influenza A Virus, H7N9 Subtype - drug effects; inhibitors; Life Sciences & Biomedicine; lipids; Madin Darby Canine Kidney Cells; Pharmacology; Pharmacology & Pharmacy; Phospholipase D - antagonists & inhibitors; Phospholipase D - metabolism; phospholipase D; PLD2; Protein Binding; Rats; Rats, Sprague-Dawley; Science & Technology; Spiro Compounds - chemistry; Spiro Compounds - pharmacokinetics; Spiro Compounds - toxicity; Structure-Activity Relationship; antivirals; inhibitors; lipids; DESIGN; PHOSPHOLIPASE-D; phospholipaseD; CHEMICAL MODULATION; PLD2; HALOPEMIDE; phospholipase D
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.201402333

Further chemical optimization of the halopemide‐derived family of dual phospholipase D1/2 (PLD1/2) inhibitors afforded ML395 (VU0468809), a potent, >80‐fold PLD2 selective allosteric inhibitor (cellular PLD1, IC50>30 000 nM; cellular PLD2, IC50=360 nM). Moreover, ML395 possesses an attractive in vitro DMPK profile, improved physiochemical properties, ancillary pharmacology (Eurofins Panel) cleaner than any other reported PLD inhibitor, and has been found to possess interesting activity as an antiviral agent in cellular assays against a range of influenza strains (H1, H3, H5 and H7). PLD2, viral killer! Focused optimization efforts led to the development of ML395, a potent (IC50=360 nM) and >80‐fold selective phospholipase D2 (PLD2) inhibitor with improved physiochemical properties, no cytotoxicity, high CNS penetration and a favorable DMPK profile. The PLD2 inhibitors displayed pan‐anti‐influenza activity across various influenza strains (H1N1, H3N2, H5N1, H7N9).