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6-(Ar)Alkylamino-Substituted Uracil Derivatives: Lipid Mimetics with Potent Activity at the Orphan G Protein-Coupled Receptor 84 (GPR84)
ACS Omega ( IF 3.7 ) Pub Date : 2018-03-20 00:00:00 , DOI: 10.1021/acsomega.7b02092
Thanigaimalai Pillaiyar 1 , Meryem Köse 1 , Vigneshwaran Namasivayam 1 , Katharina Sylvester 1 , Gleice Borges 1 , Dominik Thimm 1 , Ivar von Kügelgen 2 , Christa E. Müller 1
Affiliation  

GPR84, a Gi protein-coupled receptor that is activated by medium-chain (hydroxy)fatty acids, appears to play an important role in inflammation, immunity, and cancer. Recently, 6-octylaminouracil (4) has been reported to act as an agonist at GPR84. Here, we describe the synthesis of 69 derivatives and analogs of 4, 66 of which represent new compounds. They were evaluated in (a) cyclic adenosine monophosphate accumulation and (b) β-arrestin assays in human GPR84-expressing cells. Potent nonbiased as well as G protein-biased agonists were developed, e.g., 6-hexylamino-2,4(1H,3H)-pyrimidinedione (20, PSB-1584, EC50 5.0 nM (a), 3.2 nM (b), bias factor: 0) and 6-((p-chloro- and p-bromo-phenylethyl)amino)-2,4(1H,3H)-pyrimidinedione (47, PSB-16434, EC50 7.1 nM (a), 520 nM (b), bias factor: 1.9 = 79-fold Gi pathway-selective; 48, PSB-17365, EC50 2.5 nM (a), 100 nM (b), bias factor 1.3 = 20-fold selective), which were selective versus other free fatty acid-activated receptors. Compounds 20 and 48 were found to be metabolically stable upon incubation with human liver microsomes. A pharmacophore model was created on the basis of structurally diverse lipidlike GPR84 agonists.

中文翻译:

6-(Ar)烷基氨基取代的尿嘧啶衍生物:在孤儿G蛋白偶联受体84(GPR84)上具有有效活性的脂质模拟物

GPR84是一种被Gi蛋白偶联的受体,被中链(羟基)脂肪酸激活,似乎在炎症,免疫和癌症中起着重要作用。最近,据报道6-辛基氨基尿嘧啶(4)在GPR84上起激动剂的作用。在这里,我们描述了69个衍生物和4的类似物的合成,其中66个代表新化合物。在(a)表达人GPR84的细胞中,通过(a)环状单磷酸腺苷蓄积和(b)β-arrestin测定法对它们进行了评估。开发了有效的非偏性和G蛋白偏性激动剂,例如6-己氨基-2,4(1 H,3 H)-嘧啶二酮(20,PSB-1584,EC 505.0 nM(a),3.2 nM(b),偏倚系数:0)和6-((对-氯-和对-溴-苯甲基)氨基)-2,4(1 H,3 H)-嘧啶二酮(47,PSB-16434,EC 50 7.1 nM(a),520 nM(b),偏倚系数:1.9 = 79倍G i途径选择性;48,PSB-17365,EC 50 2.5 nM(a),100 nM( b),偏倚因子1.3 =选择性的20倍),与其他游离脂肪酸激活的受体相比具有选择性。化合物2048在与人肝微粒体温育后,发现其在代谢上是稳定的。在结构多样的类脂质GPR84激动剂的基础上创建了一个药效团模型。
更新日期:2018-03-20
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