Investigating the Structure-Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists.
Investigating the Structure-Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists.
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DOI：
10.1021/acs.jmedchem.2c00804
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发表时间：
2022-08-25
影响因子：
7.3
通讯作者：
Jamieson, Andrew G.
中科院分区：
文献类型：
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作者：
Mahindra, Amit;Jenkins, Laura;Marsango, Sara;Huggett, Mark;Huggett, Margaret;Robinson, Lindsay;Gillespie, Jonathan;Rajamanickam, Muralikrishnan;Morrison, Angus;McElroy, Stuart;Tikhonova, Irina G.;Milligan, Graeme;Jamieson, Andrew G.
G蛋白偶联受体84(GPR84)是一种致炎孤儿G蛋白偶联受体，参与多种炎症性和纤维化疾病。已经开发了几种针对GPR84的激动剂和拮抗剂配体；然而，一种进入第二阶段临床试验的非竞争性受体阻滞剂未能证明疗效。需要新的高质量的拮抗剂来研究GPR84的病理生理作用，并确认GPR84作为治疗靶点。我们先前报道了一种新的三嗪GPR84竞争拮抗剂1的发现。在这里，我们描述了拮抗剂1的广泛的构效关系(SAR)，并存在于支持突变的电子对接研究中，揭示了这种类型的邻位构型拮抗剂的潜在结合姿势。先导化合物42是一种有效的GPR84拮抗剂，具有良好的药代动力学(PK)特征，适合于进一步的药物开发。
G-protein-coupled receptor 84 (GPR84) is a proinflammatory orphan G-protein-coupled receptor implicated in several inflammatory and fibrotic diseases. Several agonist and antagonist ligands have been developed that target GPR84; however, a noncompetitive receptor blocker that was progressed to phase II clinical trials failed to demonstrate efficacy. New high-quality antagonists are required to investigate the pathophysiological role of GPR84 and to validate GPR84 as a therapeutic target. We previously reported the discovery of a novel triazine GPR84 competitive antagonist 1. Here, we describe an extensive structure–activity relationship (SAR) of antagonist 1 and also present in silico docking with supporting mutagenesis studies that reveals a potential binding pose for this type of orthosteric antagonist. Lead compound 42 is a potent GPR84 antagonist with a favorable pharmacokinetic (PK) profile suitable for further drug development.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
7.3
作者：
通讯作者：
--
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.
影响因子：
3.5
作者：
Gianella-Borradori M;Christou I;Bataille CJ;Cross RL;Wynne GM;Greaves DR;Russell AJ
通讯作者：
Russell AJ
作为有效 GPR84 激动剂的 2-烷基嘧啶-4,6-二醇和 6-烷基吡啶-2,4-二醇的设计和合成。
影响因子：
4.2
作者：
Liu, Yang;Zhang, Qing;Nan, Fa-Jun
通讯作者：
Nan, Fa-Jun