Design, Synthesis And Structure-Activity Relationship Studies Of GPR84 Agonists

GPR84 belongs to free fatty acid receptors (FFAR) and it is mainly activated by MCFA(C9-14). The transmembrane domains contain the most sequence conservation among the rhodopsin family and are characterized by a stretch of 25-35 consecutive residues. GPR84 is highly expressed in human bone marrow, and to a lesser extent, in the peripheral leukocytes and lungs. In physiological conditions, the expression of GPR84 is low, but it can be increased remarkably in monocytes/macrophages upon activation by lipopolysaccharide. Several recent studies also showed that GPR84 plays a significant role in inflammation. Many disease have much to do with inflammation, and some GPR84 modulators are reported useful to cure some disease by modulating inflammation. In this thesis, we concentrated on the designing, synthesising and Structure-Activity Relationship Studies of GPR84 agonists, and a series of high potent GPR84 agonists had been synthesized. Such GPR84 agonists with novel chemical structure would be valuable tools for the study of the physiological functions of GPR84.we carried out a high-throughput screening of 160,000 small-molecule compounds using a calcium mobilization assay with HEK293 cells expressing GPR84. The screening resulted in the identification of compound 3 as a GPR84 agonist with an ECso of 139 nM, which is 4.7-fold more potent than the reported agonist 6-OAU (EC50=653 nM). By comparing, we found that Compound 3 shares some structural similarities with 6-OAU. Both compounds have a pyrimidine ring and an alkyl side chain. The only differences between the structures are the orientation of the pyrimidine ring and the minor variation in the side chain. Considering the potential for activity improvement, a structure optimization was carried out in four aspects to elucidate the structure-activity relationship (SAR) of this scaffold:(A) the length of the alkyl chain, (B) substitutions on the pyrimidine ring, (C) the type of the linker group, (D) replacement of the pyrimidine ring. And 52 compounds had got, especially compounds 45 with an EC50 of 0.189 nM, which is approximately a 730-fold increase over hit 3 and 3400-fold more potent than 6-OAU. Such GPR84 agonists with novel chemical structure would be valuable tools for the study of the physiological functions of GPR84.And, pave the way for the studying of the relationship of GPR84 and relate diseases.