Investigating the structure–activity relationship of 1,2,4-triazine G-protein-coupled receptor 84 (GPR84) antagonists
| Autor: | Amit Mahindra, Laura Jenkins, Sara Marsango, Mark Huggett, Margaret Huggett, Lindsay Robinson, Jonathan Gillespie, Muralikrishnan Rajamanickam, Angus Morrison, Stuart McElroy, Irina G. Tikhonova, Graeme Milligan, Andrew G. Jamieson |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | 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 & Jamieson, A G 2022, ' Investigating the Structure-Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists ', Journal of Medicinal Chemistry, vol. 65, no. 16, pp. 11270–11290 . https://doi.org/10.1021/acs.jmedchem.2c00804 |
| ISSN: | 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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