title: Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part I: Impact of alternative halogenated privileged structures for PLD1 specificity.
abstract: This Letter describes the synthesis and structure-activity-relationships (SAR) of isoform-selective PLD inhibitors. By virtue of the installation of alternative halogenated piperidinyl benzimidazolone privileged structures, in combination with a key (S)-methyl group, novel PLD inhibitors with low nM potency and unprecedented levels of PLD1 isoform selectivity (approximately 1700-fold) over PLD2 were developed.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Jana A
authors.initials: JA
authors.lastname: Lewis
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Scott
authors.forename: Robert
authors.initials: R
authors.lastname: Lavieri
authors.forename: Jason R
authors.initials: JR
authors.lastname: Buck
authors.forename: Paige E
authors.initials: PE
authors.lastname: Selvy
authors.forename: Sydney L
authors.initials: SL
authors.lastname: Stoops
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Armstrong
authors.forename: H Alex
authors.initials: HA
authors.lastname: Brown
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004294:Domperidone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054879:Halogenation; D006801:Humans; D010739:Phospholipase D / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; C014353:benzimidazolone; D004294:Domperidone; D010739:Phospholipase D; C106801:phospholipase D1