H. Alex Brown
Principle Investigator; Professor of Pharmacology, Chemistry, and Biochemistry; Associate Director, VICB;
Last active: 2/12/2015

Further evaluation of novel structural modifications to scaffolds that engender PLD isoform selective inhibition.

O'Reilly MC, Scott SA, Brown HA, Lindsley CW
Bioorg Med Chem Lett. 2014 24 (24): 5553-5557

PMID: 25466173 · PMCID: PMC4535313 · DOI:10.1016/j.bmcl.2014.11.017

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.

Copyright © 2014 Elsevier Ltd. All rights reserved.

MeSH Terms (12)

Animals Benzimidazoles Enzyme Inhibitors HEK293 Cells Humans Kinetics Microsomes Phospholipase D Piperidines Protein Binding Rats Structure-Activity Relationship

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