Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University and Oncode Institute, 2300 RA Leiden, Netherlands.
J Med Chem. 2021 Jan 14;64(1):481-515. doi: 10.1021/acs.jmedchem.0c01441. Epub 2020 Dec 31.
-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 .
酰基磷脂酰乙醇胺磷脂酶 D（NAPE-PLD）被认为是生物合成 - 酰基乙醇胺（NAE）的主要酶，NAE 是一类生物活性脂质介质。此前，我们报道了 -(环丙基甲基）-6-((()-3-羟基吡咯烷-1-基）-2-((()-3-苯基哌啶-1-基）嘧啶-4-甲酰胺（，）作为第一个有效的、选择性的 NAPE-PLD 抑制剂，可降低自由活动小鼠大脑中的 NAE，并调节情绪行为[Mock，2020，16，667-675]。在这里，我们描述了嘧啶-4-甲酰胺作为 NAPE-PLD 抑制剂的库的构效关系（SAR），这导致了的鉴定。高内涵筛选命中物在三个不同的取代基上进行修饰，以优化其效力和脂溶性。用（）-3-苯基哌啶代替 - 甲基苯乙胺基团可使构象受限，从而使抑制效力提高 3 倍。用（）-3-羟基吡咯烷取代吗啉取代基可降低脂溶性，并使活性进一步提高 10 倍，得到具有纳摩尔效力的药物样特性的抑制剂。是一种合适的药理学工具化合物，可用于研究 NAPE-PLD 功能和。
