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Small Molecules (Tool Compounds)

NAPE-Phospholipase D inhibitor (LEI-401) small molecule (tool compound)

Invented by Mario Van Der Stelt
Invented at Leiden University and Leiden University Medical Center
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Here is described the structure–activity relationship (SAR) of a library of pyrimidine-4-carboxamides as inhibitors of NAPE-PLD that led to the identification of LEI-401. A high-throughput screening hit was modified at three different substituents to optimize its potency and lipophilicity. Conformational restriction of an N-methylphenethylamine group by replacement with an (S)-3-phenylpiperidine increased the inhibitory potency 3-fold. Exchange of a morpholine substituent for an (S)-3-hydroxypyrrolidine reduced the lipophilicity and further increased activity by 10-fold, affording LEI-401 as a nanomolar potent inhibitor with drug-like properties. LEI-401 is a suitable pharmacological tool compound to investigate NAPE-PLD function in vitro and in vivo. Adapted from the abstract of Mock ED, Kotsogianni I, Driever WPF, Fonseca CS, Vooijs JM, den Dulk H, van Boeckel CAA, van der Stelt M. Structure-Activity Relationship Studies of Pyrimidine-4-Carboxamides as Inhibitors of N-Acylphosphatidylethanolamine Phospholipase D. J Med Chem. 2021 Jan 14;64(1):481-515. doi: 10.1021/acs.jmedchem.0c01441. Epub 2020 Dec 31. PMID: 33382264; PMCID: PMC7816197.
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Catalogue Number 160829
Antigen/Gene or Protein Targets N-acyl phosphatidylethanolamine-specific phospholipase D
Synonyms N-acyl phosphatidylethanolamine-specific phospholipase D inhibitor, LEI-401
Type Inhibitor
Relevance D-type phospholipase that hydrolyzes N-acyl-phosphatidylethanolamines (NAPEs) to produce bioactive N-acylethanolamines/fatty acid ethanolamides (NAEs/FAEs) and phosphatidic acid. Cleaves the terminal phosphodiester bond of diacyl- and alkenylacyl-NAPEs, primarily playing a role in the generation of long-chain saturated and monounsaturated NAEs in the brain._x000D_
May control NAPE homeostasis in dopaminergic neuron membranes and regulate neuron survival, partly through RAC1 activation. As a regulator of lipid metabolism in the adipose tissue, mediates the crosstalk between adipocytes, gut microbiota and immune cells to control body temperature and weight. In particular, regulates energy homeostasis by promoting cold-induced brown or beige adipocyte differentiation program to generate heat from fatty acids and glucose. Has limited D-type phospholipase activity toward N-acyl lyso-NAPEs
On Target IC50 27 nM
Selectivity IC50> 10uM for CB1R & CB2R, FAAH, PLA2G4E, DAGL, MAGL, ABHD6
Molecular Formula C24H31N5O2
Key Attributes Reduces N-acylethanolamines levels, including anandamide, in cells and mouse brain
lUPAC N-(Cyclopropylmethyl)-6-((S)-3-hydroxypyrrolidin-1-yl)-2-((S)-3-phenylpiperidin-1-yl)pyrimidine-4-carboxamide.
Molecular Weight (g/mol) 422
In vivo applications good bioavailability F (i.p.) = 48 % and brain penetrant
In vitro applications good cellular penetration
Solubility 1.7 mg/L
Research Area Neurobiology, Metabolism
Notes Mock et al., Nature Chemical Biology, 2020, 16, 667-675

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Mock et al. 2021. J Med Chem. 64(1):481-515. PMID: 33382264.

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References: 1 entry

Mock et al. 2021. J Med Chem. 64(1):481-515. PMID: 33382264.

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