title: Further evaluation of novel structural modifications to scaffolds that engender PLD isoform selective inhibition.
abstract: This Letter describes the on-going SAR efforts based on two scaffolds, a PLD1-biased piperidinyl benzimidazolone and a PLD2-biased piperidinyl triazaspirone, with the goal of enhancing PLD inhibitory potency and isoform selectivity. Here, we found that addition of an α-methyl moiety within the PLD2-biased piperidinyl triazaspirone scaffold abolished PLD2 preference, while the incorporation of substituents onto the piperidine moiety of the PLD1-biased piperidinyl benzimidazolone, or replacement with a bioisosteric [3.3.0] core, generally retained PLD1 preference, but at diminished significance. The SAR uncovered within these two allosteric PLD inhibitor series further highlights the inherent challenges of developing isoform selective PLD inhibitors.
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: O'Reilly
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Scott
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.|Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: H Alex
authors.initials: HA
authors.lastname: Brown
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.|Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.|Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA.|Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.|Vanderbilt Institute of Chemical Biology, Vanderbilt University/ Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000378:metabolism; D010739:Phospholipase D / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D010880:Piperidines; C014353:benzimidazolone; C032727:piperidine; C105606:phospholipase D2; D010739:Phospholipase D; C106801:phospholipase D1
keywords: Inhibitors; Isoform; Phosphodiesterase; Phospholipase D (PLD)