Design and synthesis of isoform-selective phospholipase D (PLD) inhibitors. Part II. Identification of the 1,3,8-triazaspiro[4,5]decan-4-one privileged structure that engenders PLD2 selectivity

Abstract

This Letter describes the synthesis and structure–activity relationships (SAR) of isoform-selective PLD inhibitors. By virtue of the installation of a 1,3,8-triazaspiro[4,5]decan-4-one privileged structure, PLD inhibitors with nanomolar potency and an unprecedented 40-fold selectivity for PLD2 over PLD1 were developed. Interestingly, SAR for this diverged from our earlier efforts, and dual PLD1/2 inhibitors were also discovered within this series.

Drugs for Allosteric Sites on Receptors

“…The benzimidazolone core favored PLD1 inhibition, and a chiral ( S )-methyl group on the ethylene diamine linkers further enhanced PLD1 inhibition. Preferential PLD2 inhibition could be achieved with a bioisoteric triazaspirone scaffold, leading to the compound VU0364739 ( 17 , Figure 5 c ), which displays a 75-fold preference for inhibition of PLD2 over PLD1 (55, 56). Both VU0359595 and VU0364739 ( 16 and 17 , Figure 5 c ), as well as more advanced PLD inhibitors in these series (57), displayed significantly improved drug metabolism and pharmacokinetic properties while eliminating biogenic amine activity.…”

Chemical modulation of glycerolipid signaling and metabolic pathways

“…2B) [86]. Since this study, we identified PLD2-preferring compounds with lower PLD2 potency and minimal PLD1 activity; these compounds also have improved overall ancillary pharmacology (VU0285655 and ML298) [87, 88]. Our current studies focus primarily on improving the drug metabolism and pharmacokinetic properties of PLD inhibitors, enhancing overall dual isoform potency, and achieving better PLD2 selectivity [88].…”

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

“…1,2,5,6 This series was plagued with ancillary pharmacology, due to the GPCR privileged structure, and poor metaboic stability (MET ID indicated oxidative metabolism on the central piperidine ring). 5,6,9 In an attempt to address these issues, we elected to install a methyl group α to the piperidine nitrogen to block oxidative metabolism (as in 9 and 10 ), as well as a β-fluorine atom (as in 11 ) to modulate pK a and potentially improve ancillary pharmacology at biogenic amine targets. The requisite functionalized piperidine benzimidazolones were prepared as previously described following literature routes 5,6,14 and then elaborated via a reported variation on Scheme 1.…”

“…5,6,9 In an attempt to address these issues, we elected to install a methyl group α to the piperidine nitrogen to block oxidative metabolism (as in 9 and 10 ), as well as a β-fluorine atom (as in 11 ) to modulate pK a and potentially improve ancillary pharmacology at biogenic amine targets. The requisite functionalized piperidine benzimidazolones were prepared as previously described following literature routes 5,6,14 and then elaborated via a reported variation on Scheme 1. 5,6 While we were excited to note that these modifications to the piperdine core retained PLD inhbitiory activity, the compounds were less potent and possessed diminished PLD1 selectivity as compared to the unsubstitiuted congeners ( Fig.…”

“…The requisite functionalized piperidine benzimidazolones were prepared as previously described following literature routes 5,6,14 and then elaborated via a reported variation on Scheme 1. 5,6 While we were excited to note that these modifications to the piperdine core retained PLD inhbitiory activity, the compounds were less potent and possessed diminished PLD1 selectivity as compared to the unsubstitiuted congeners ( Fig. 4 ); thus, they did not represent a path forward towards improved in vivo tools.…”