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

-Acylphosphatidylethanolamine phospholipase D (NAPE-PLD) is regarded as the main enzyme responsible for the biosynthesis of -acylethanolamines (NAEs), a family of bioactive lipid mediators. Previously, we reported -(cyclopropylmethyl)-6-(()-3-hydroxypyrrolidin-1-yl)-2-(()-3-phenylpiperidin-1-yl)pyrimidine-4-carboxamide (, ) as the first potent and selective NAPE-PLD inhibitor that decreased NAEs in the brains of freely moving mice and modulated emotional behavior [Mock , 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 . A high-throughput screening hit was modified at three different substituents to optimize its potency and lipophilicity. Conformational restriction of an -methylphenethylamine group by replacement with an ()-3-phenylpiperidine increased the inhibitory potency 3-fold. Exchange of a morpholine substituent for an ()-3-hydroxypyrrolidine reduced the lipophilicity and further increased activity by 10-fold, affording as a nanomolar potent inhibitor with drug-like properties. is a suitable pharmacological tool compound to investigate NAPE-PLD function and .