Isoform selective PLD inhibition by novel, chiral 2,8-diazaspiro[4.5]decan-1-one derivatives

Alex G Waterson; Sarah A Scott; Nathan R Kett; Anna L Blobaum; H Alex Brown; Craig W Lindsley

doi:10.1016/j.bmcl.2018.10.033

Isoform selective PLD inhibition by novel, chiral 2,8-diazaspiro[4.5]decan-1-one derivatives

Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3670-3673. doi: 10.1016/j.bmcl.2018.10.033. Epub 2018 Oct 22.

Authors

Alex G Waterson¹, Sarah A Scott², Nathan R Kett³, Anna L Blobaum⁴, H Alex Brown⁵, Craig W Lindsley⁶

Affiliations

¹ Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt Institute of Chemical Biology, Vanderbilt University/Vanderbilt University Medical Center, Nashville, TN 37232, USA.
² Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
³ Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA.
⁴ 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.
⁵ Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Biochemistry, Vanderbilt University, 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.
⁶ 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; Department of Biochemistry, Vanderbilt University, 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. Electronic address: craig.lindsley@vanderbilt.edu.

PMID: 30528979
DOI: 10.1016/j.bmcl.2018.10.033

Abstract

This letter describes the on-going SAR efforts to develop PLD1, PLD2 and dual PLD1/2 inhibitors with improved physiochemical and disposition properties as well as securing intellectual property position. Previous PLD inhibitors, based on a triazaspiro[4.5]decanone core proved to be highly selective PLD2 inhibitors, but with low plasma free fraction (rat, human f_u < 0.03), high predicted hepatic clearance (rat CL_hep > 65 mL/min/kg) and very short half-lives in vivo (t_1/2 < 0.15 h). Removal of a nitrogen atom from this core generated a 2,8-diazaspiro[4.5]decanone core, harboring a new chiral center, as well as increased sp³ character. This new core demonstrated enantioselective inhibition of the individual PLD isoforms, enhanced free fraction (rat, human f_u < 0.13), engendered moderate predicted hepatic clearance (rat CL_hep ∼ 43 mL/min/kg), improved half-lives in vivo (t_1/2 > 3 h), and led to the first issued US patent claiming composition of matter for small molecule PLD inhibitors.

Keywords: Inhibitors; Isoform; PLD; Phosphodiesterase; Phospholipase D.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacokinetics
HEK293 Cells
Half-Life
Humans
Inhibitory Concentration 50
Phospholipase D / antagonists & inhibitors
Phospholipase D / metabolism*
Protein Isoforms / antagonists & inhibitors
Protein Isoforms / metabolism
Rats
Spiro Compounds / chemical synthesis
Spiro Compounds / chemistry*
Spiro Compounds / pharmacokinetics
Stereoisomerism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Protein Isoforms
Spiro Compounds
Phospholipase D