Mahindra, A. et al. (2022) Investigating the structure–activity relationship of 1,2,4-triazine G-protein-coupled receptor 84 (GPR84) antagonists. Journal of Medicinal Chemistry, 65(16), pp. 11270-11290. (doi: 10.1021/acs.jmedchem.2c00804) (PMID:35948061) (PMCID:PMC9421653)
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Abstract
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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Milligan, Professor Graeme and Jenkins, Mrs Laura and Jamieson, Professor Andrew and Marsango, Dr Sara and Mahindra, Dr Amit |
| Authors: | Mahindra, A., Jenkins, L., Marsango, S., Huggett, M., Huggett, M., Robinson, L., Gillespie, J., Rajamanickam, M., Morrison, A., McElroy, S., Tikhonova, I. G., Milligan, G., and Jamieson, A. G. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences College of Science and Engineering > School of Chemistry |
| Journal Name: | Journal of Medicinal Chemistry |
| Publisher: | American Chemical Society |
| ISSN: | 0022-2623 |
| ISSN (Online): | 1520-4804 |
| Published Online: | 10 August 2022 |
| Copyright Holders: | Copyright © 2022 The Authors |
| First Published: | First published in Journal of Medicinal Chemistry 65(16): 11270-11290 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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