Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part I: Impact of alternative halogenated privileged structures for PLD1 specificity.
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.
Lewis
Jana A
JA
Department of Pharmacology, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN 37232, USA.
Scott
Sarah A
SA
Lavieri
Robert
R
Buck
Jason R
JR
Selvy
Paige E
PE
Stoops
Sydney L
SL
Armstrong
Michelle D
MD
Brown
H Alex
HA
Lindsley
Craig W
CW
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
D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; C014353:benzimidazolone; D004294:Domperidone; D010739:Phospholipase D; C106801:phospholipase D1