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Modulation of the G-Protein-Coupled Receptor 84 (GPR84) by Agonists and Antagonists
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-02 , DOI: 10.1021/acs.jmedchem.0c01378 Lin-Hai Chen 1 , Qing Zhang 2 , Xin Xie 2 , Fa-Jun Nan 1, 3
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-02 , DOI: 10.1021/acs.jmedchem.0c01378 Lin-Hai Chen 1 , Qing Zhang 2 , Xin Xie 2 , Fa-Jun Nan 1, 3
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Since the discovery of medium-chain fatty acids as GPR84 ligands, significant advancements have been made in the development of GPR84 agonists and antagonists. Most agonists have lipid-like structures except for 3,3′-diindolylmethane (DIM), which acts as an allosteric agonist. GPR84 activation in macrophages leads to increased cytokine secretion, chemotaxis, and phagocytosis, revealing the proinflammatory role of GPR84 associated with various inflammatory responses. Three GPR84 antagonists (S)-2-((1,4-dioxan-2-yl)methoxy)-9-(cyclopropylethynyl)-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-4-one (GLPG1205), sodium 2-(3-pentylphenyl)acetate (PBI-4050), and sodium 2-(3,5-dipentylphenyl)acetate (PBI-4547) have displayed therapeutic effects in animal models of several inflammatory and fibrotic diseases and are being evaluated in clinical studies. Although GLPG1205 has failed in a clinical trial for ulcerative colitis, it is undergoing another phase II clinical study for idiopathic pulmonary fibrosis. Further studies are needed to resolve the GPR84 structure, identify more endogenous ligands, elucidate their physiological and pathological roles, and fulfill the therapeutic potential of GPR84 antagonists and agonists.
中文翻译：
激动剂和拮抗剂调节G蛋白偶联受体84（GPR84）
自发现中链脂肪酸作为GPR84配体以来，GPR84激动剂和拮抗剂的开发已取得重大进展。除3,3'-二吲哚基甲烷（DIM）外，大多数激动剂均具有类脂质结构，而后者是一种变构激动剂。巨噬细胞中的GPR84激活导致细胞因子分泌，趋化性和吞噬作用增加，从而揭示了GPR84与各种炎症反应相关的促炎作用。三种GPR84拮抗剂（S）-2-（（1,4-二恶烷-2-基）甲氧基）-9-（环丙基乙炔基）-6,7-二氢-4 H-嘧啶[6,1- a]异喹啉-4-酮（GLPG1205），2-（3-戊基苯基）乙酸钠（PBI-4050）和2-（3,5-二戊基苯基）乙酸钠（PBI-4547）在以下动物模型中显示出治疗效果几种炎性和纤维化疾病，正在临床研究中进行评估。尽管GLPG1205在溃疡性结肠炎的临床试验中失败了，但它正在针对特发性肺纤维化进行另一项II期临床研究。需要进一步的研究来解决GPR84的结构，鉴定更多的内源性配体，阐明其生理和病理作用，并发挥GPR84拮抗剂和激动剂的治疗潜力。
更新日期：2020-12-24
中文翻译：
激动剂和拮抗剂调节G蛋白偶联受体84（GPR84）
自发现中链脂肪酸作为GPR84配体以来，GPR84激动剂和拮抗剂的开发已取得重大进展。除3,3'-二吲哚基甲烷（DIM）外，大多数激动剂均具有类脂质结构，而后者是一种变构激动剂。巨噬细胞中的GPR84激活导致细胞因子分泌，趋化性和吞噬作用增加，从而揭示了GPR84与各种炎症反应相关的促炎作用。三种GPR84拮抗剂（S）-2-（（1,4-二恶烷-2-基）甲氧基）-9-（环丙基乙炔基）-6,7-二氢-4 H-嘧啶[6,1- a]异喹啉-4-酮（GLPG1205），2-（3-戊基苯基）乙酸钠（PBI-4050）和2-（3,5-二戊基苯基）乙酸钠（PBI-4547）在以下动物模型中显示出治疗效果几种炎性和纤维化疾病，正在临床研究中进行评估。尽管GLPG1205在溃疡性结肠炎的临床试验中失败了，但它正在针对特发性肺纤维化进行另一项II期临床研究。需要进一步的研究来解决GPR84的结构，鉴定更多的内源性配体，阐明其生理和病理作用，并发挥GPR84拮抗剂和激动剂的治疗潜力。
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