Discovery of a Highly Selective PLD2 Inhibitor (ML395): A New Probe with Improved Physiochemical Properties and Broad‐Spectrum Antiviral Activity against Influenza Strains |
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| Authors: | Matthew C. O'Reilly Thomas H. Oguin III Dr. Sarah A. Scott Prof. Paul G. Thomas Dr. Charles W. Locuson Ryan D. Morrison Prof. J. Scott Daniels Prof. H. Alex Brown Prof. Craig W. Lindsley |
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| Affiliation: | 1. Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt Specialized Chemistry Center (MLPCN), Vanderbilt University Medical Center, Nashville, TN 37232‐6600 (USA);2. Department of Immunology, St. Jude Children's Hospital, Memphis, TN 38105 (USA) |
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| Abstract: | 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). |
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| Keywords: | antivirals inhibitors lipids phospholipase D PLD2 |
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