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

• Published in: Journal of medicinal chemistry Vol. 64; no. 1; pp. 481 - 515
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 14.01.2021; American Chemical Society
• Subjects: Amides - chemistry; Carboxylic Acids - chemistry; Carboxylic Acids - pharmacology; Chemistry, Medicinal; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Phosphatidylethanolamines - chemistry; Phospholipases - antagonists & inhibitors; Phospholipases - chemistry; Pyrimidines - chemistry; Pyrimidines - pharmacology; Science & Technology; Structure-Activity Relationship; PHOSPHATIDYLETHANOLAMINE; BIOSYNTHESIS; ANANDAMIDE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01441

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)-64(S)-3-hydroxypyrroli din-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 [Mock et al. Nat Chem. Biol., 2020, 16, 667-675]. 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.