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Structure–Activity Relationship Studies of Pyrimidine-4-Carboxamides as Inhibitors of N-Acylphosphatidylethanolamine Phospholipase D

[Image: see text] N-Acylphosphatidylethanolamine phospholipase D (NAPE-PLD) is regarded as the main enzyme responsible for the biosynthesis of N-acylethanolamines (NAEs), a family of bioactive lipid mediators. Previously, we reported N-(cyclopropylmethyl)-6-((S)-3-hydroxypyrrolidin-1-yl)-2-((S)-3-ph...

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Autores principales: Mock, Elliot D., Kotsogianni, Ioli, Driever, Wouter P. F., Fonseca, Carmen S., Vooijs, Jelle M., den Dulk, Hans, van Boeckel, Constant A. A., van der Stelt, Mario
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816197/
https://www.ncbi.nlm.nih.gov/pubmed/33382264
http://dx.doi.org/10.1021/acs.jmedchem.0c01441
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author Mock, Elliot D.
Kotsogianni, Ioli
Driever, Wouter P. F.
Fonseca, Carmen S.
Vooijs, Jelle M.
den Dulk, Hans
van Boeckel, Constant A. A.
van der Stelt, Mario
author_facet Mock, Elliot D.
Kotsogianni, Ioli
Driever, Wouter P. F.
Fonseca, Carmen S.
Vooijs, Jelle M.
den Dulk, Hans
van Boeckel, Constant A. A.
van der Stelt, Mario
author_sort Mock, Elliot D.
collection PubMed
description [Image: see text] N-Acylphosphatidylethanolamine phospholipase D (NAPE-PLD) is regarded as the main enzyme responsible for the biosynthesis of N-acylethanolamines (NAEs), a family of bioactive lipid mediators. Previously, we reported N-(cyclopropylmethyl)-6-((S)-3-hydroxypyrrolidin-1-yl)-2-((S)-3-phenylpiperidin-1-yl)pyrimidine-4-carboxamide (1, LEI-401) as the first potent and selective NAPE-PLD inhibitor that decreased NAEs in the brains of freely moving mice and modulated emotional behavior [ MockNat Chem. Biol., 2020, 16, 667−67532393901]. Here, we describe 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.
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spelling pubmed-78161972021-01-21 Structure–Activity Relationship Studies of Pyrimidine-4-Carboxamides as Inhibitors of N-Acylphosphatidylethanolamine Phospholipase D Mock, Elliot D. Kotsogianni, Ioli Driever, Wouter P. F. Fonseca, Carmen S. Vooijs, Jelle M. den Dulk, Hans van Boeckel, Constant A. A. van der Stelt, Mario J Med Chem [Image: see text] N-Acylphosphatidylethanolamine phospholipase D (NAPE-PLD) is regarded as the main enzyme responsible for the biosynthesis of N-acylethanolamines (NAEs), a family of bioactive lipid mediators. Previously, we reported N-(cyclopropylmethyl)-6-((S)-3-hydroxypyrrolidin-1-yl)-2-((S)-3-phenylpiperidin-1-yl)pyrimidine-4-carboxamide (1, LEI-401) as the first potent and selective NAPE-PLD inhibitor that decreased NAEs in the brains of freely moving mice and modulated emotional behavior [ MockNat Chem. Biol., 2020, 16, 667−67532393901]. Here, we describe 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. American Chemical Society 2020-12-31 2021-01-14 /pmc/articles/PMC7816197/ /pubmed/33382264 http://dx.doi.org/10.1021/acs.jmedchem.0c01441 Text en © 2020 The Authors. Published by American Chemical Society This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License (http://pubs.acs.org/page/policy/authorchoice_ccbyncnd_termsofuse.html) , which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes.
spellingShingle Mock, Elliot D.
Kotsogianni, Ioli
Driever, Wouter P. F.
Fonseca, Carmen S.
Vooijs, Jelle M.
den Dulk, Hans
van Boeckel, Constant A. A.
van der Stelt, Mario
Structure–Activity Relationship Studies of Pyrimidine-4-Carboxamides as Inhibitors of N-Acylphosphatidylethanolamine Phospholipase D
title Structure–Activity Relationship Studies of Pyrimidine-4-Carboxamides as Inhibitors of N-Acylphosphatidylethanolamine Phospholipase D
title_full Structure–Activity Relationship Studies of Pyrimidine-4-Carboxamides as Inhibitors of N-Acylphosphatidylethanolamine Phospholipase D
title_fullStr Structure–Activity Relationship Studies of Pyrimidine-4-Carboxamides as Inhibitors of N-Acylphosphatidylethanolamine Phospholipase D
title_full_unstemmed Structure–Activity Relationship Studies of Pyrimidine-4-Carboxamides as Inhibitors of N-Acylphosphatidylethanolamine Phospholipase D
title_short Structure–Activity Relationship Studies of Pyrimidine-4-Carboxamides as Inhibitors of N-Acylphosphatidylethanolamine Phospholipase D
title_sort structure–activity relationship studies of pyrimidine-4-carboxamides as inhibitors of n-acylphosphatidylethanolamine phospholipase d
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816197/
https://www.ncbi.nlm.nih.gov/pubmed/33382264
http://dx.doi.org/10.1021/acs.jmedchem.0c01441
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