title: Discovery of a highly selective PLD2 inhibitor (ML395): a new probe with improved physiochemical properties and broad-spectrum antiviral activity against influenza strains.
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).
authors.affiliation: Department of Pharmacology, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt Specialized Chemistry Center (MLPCN), Vanderbilt University Medical Center, Nashville, TN 37232-6600 (USA).
authors.forename: Matthew C
authors.initials: MC
authors.lastname: O'Reilly
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Oguin
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Scott
authors.forename: Paul G
authors.initials: PG
authors.lastname: Thomas
authors.forename: Charles W
authors.initials: CW
authors.lastname: Locuson
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morrison
authors.forename: J Scott
authors.initials: JS
authors.lastname: Daniels
authors.forename: H Alex
authors.initials: HA
authors.lastname: Brown
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D006207:Half-Life; D006801:Humans; D048289:Imidazolidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects; D064766:Influenza A Virus, H7N9 Subtype / Q000187:drug effects; D061985:Madin Darby Canine Kidney Cells; D010739:Phospholipase D / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D048289:Imidazolidines; D013141:Spiro Compounds; C000599657:VU0468809; C105606:phospholipase D2; D010739:Phospholipase D; C106801:phospholipase D1
keywords: PLD2; antivirals; inhibitors; lipids; phospholipase D