title: Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part II. Identification of the 1,3,8-triazaspiro[4,5]decan-4-one privileged structure that engenders PLD2 selectivity.
abstract: This Letter describes the synthesis and structure-activity relationships (SAR) of isoform-selective PLD inhibitors. By virtue of the installation of a 1,3,8-triazaspiro[4,5]decan-4-one privileged structure, PLD inhibitors with nanomolar potency and an unprecedented 40-fold selectivity for PLD2 over PLD1 were developed. Interestingly, SAR for this diverged from our earlier efforts, and dual PLD1/2 inhibitors were also discovered within this series.
authors.affiliation: Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lavieri
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Scott
authors.forename: Jana A
authors.initials: JA
authors.lastname: Lewis
authors.forename: Paige E
authors.initials: PE
authors.lastname: Selvy
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Armstrong
authors.forename: H
authors.initials: H
authors.lastname: Alex Brown
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D010739:Phospholipase D / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; C105606:phospholipase D2; D010739:Phospholipase D; C106801:phospholipase D1