6-(Ar)Alkylamino-Substituted Uracil Derivatives: Lipid Mimetics with Potent Activity at the Orphan G Protein-Coupled Receptor 84 (GPR84).

GPR84, a G 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 () has been reported to act as an agonist at GPR84. Here, we describe the synthesis of 69 derivatives and analogs of , 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(1,3)-pyrimidinedione (, PSB-1584, EC 5.0 nM (a), 3.2 nM (b), bias factor: 0) and 6-((-chloro- and -bromo-phenylethyl)amino)-2,4(1,3)-pyrimidinedione (, PSB-16434, EC 7.1 nM (a), 520 nM (b), bias factor: 1.9 = 79-fold G pathway-selective; , PSB-17365, EC 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 and 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.