Investigating the Structure-Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists

被引：8

作者：

Mahindra, Amit ^{[1
]}

Jenkins, Laura ^{[2
]}

Marsango, Sara ^{[2
]}

Huggett, Mark ^{[3
,4
]}

Huggett, Margaret ^{[3
,4
]}

Robinson, Lindsay ^{[3
,4
]}

Gillespie, Jonathan ^{[3
,4
]}

Rajamanickam, Muralikrishnan ^{[3
,4
]}

Morrison, Angus ^{[3
,4
]}

McElroy, Stuart ^{[3
,4
]}

Tikhonova, Irina G. ^{[5
]}

Milligan, Graeme ^{[2
]}

Jamieson, Andrew G. ^{[1
]}

机构：

[1] Univ Glasgow, Sch Chem, Glasgow G12 8QQ, Scotland

[2] Univ Glasgow, Inst Mol Cell & Syst Biol, Ctr Translat Pharmacol, Glasgow G12 8QQ, Scotland

[3] BioAscent Discovery Ltd, Newhouse, Newhouse ML1 5UH, Lanarkshire, England

[4] Univ Dundee, European Screening Ctr, Newhouse ML1 5UH, Lanarkshire, England

[5] Queens Univ Belfast, Med Biol Ctr, Sch Pharm, Belfast BT9 7BL, North Ireland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 16期

基金：

英国生物技术与生命科学研究理事会;

关键词：

DERIVATIVES; IDENTIFICATION; AGONISTS; LIGANDS;

D O I：

10.1021/acs.jmedchem.2c00804

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：11270 / 11290

页数：21