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

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

doi:10.1021/acs.jmedchem.2c00804

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

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

School of Pharmacy

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7 Citations (Scopus)

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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.

Original language	English
Pages (from-to)	11270–11290
Journal	Journal of Medicinal Chemistry
Volume	65
Issue number	16
Early online date	10 Aug 2022
DOIs	https://doi.org/10.1021/acs.jmedchem.2c00804
Publication status	Published - 25 Aug 2022

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Investigating the Structure–Activity Relationship of 1,2,4-Triazine G-Protein-Coupled Receptor 84 (GPR84) Antagonists
Copyright 2022 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 7.51 MBLicence: CC BY

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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, 65(16), 11270–11290. https://doi.org/10.1021/acs.jmedchem.2c00804

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

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.",

author = "Amit Mahindra and Laura Jenkins and Sara Marsango and Mark Huggett and Margaret Huggett and Lindsay Robinson and Jonathan Gillespie and Muralikrishnan Rajamanickam and Angus Morrison and Stuart McElroy and Tikhonova, {Irina G} and Graeme Milligan and Jamieson, {Andrew G}",

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doi = "10.1021/acs.jmedchem.2c00804",

language = "English",

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Mahindra, A, Jenkins, L, Marsango, S, Huggett, M, Huggett, M, Robinson, L, Gillespie, J, Rajamanickam, M, Morrison, A, McElroy, S, Tikhonova, IG, Milligan, G & Jamieson, AG 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

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AU - Mahindra, Amit

AU - Jenkins, Laura

AU - Marsango, Sara

AU - Huggett, Mark

AU - Huggett, Margaret

AU - Robinson, Lindsay

AU - Gillespie, Jonathan

AU - Rajamanickam, Muralikrishnan

AU - Morrison, Angus

AU - McElroy, Stuart

AU - Tikhonova, Irina G

AU - Milligan, Graeme

AU - Jamieson, Andrew G

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AB - 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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DO - 10.1021/acs.jmedchem.2c00804

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EP - 11290

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 16

ER -

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

Abstract

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