Phospholipase D (PLD) modulates the lipid second messenger phosphatidic acid (PA) by catalyzing the hydrolysis of phosphatidyl choline to PA. The two mammalian PLD isoforms share 53% sequence homology and are controlled by different regulatory mechanisms. Their distinct cellular roles have been difficult to deconstruct due to the lack of tools to affectively modulate PLD activity. Progress to define each isoenzyme's roles would be greatly enhanced if selective small-molecule inhibitors were available. This talk will detail our efforts to synthesize potent and selective PLD2 inhibitors using iterative library synthesis coupled with pharmacological characterization and DMPK data. Considerable progress has been made in developing 50-75 fold selective PLD2 inhibitors. Novel SAR has been found to greatly bias scaffolds toward PLD1 or PLD2 inhibition. These findings led to the development of potent, dual PLD1/2 inhibitors with central penetrance. This presentation will focus on the synthesis, SAR, and biological significance of PLD2 inhibitors.

Design, synthesis, and biological significance of potent, isoform selective inhibitors of phospholipase D2

244th National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.