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

Autor:	Mahindra A; School of Chemistry, University of Glasgow, Joseph Black Building, University Avenue, Glasgow G12 8QQ, U.K., Jenkins L; Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, University of Glasgow, Davidson Building, Glasgow G12 8QQ, U.K., Marsango S; Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, University of Glasgow, Davidson Building, Glasgow G12 8QQ, U.K., Huggett M; BioAscent Discovery Ltd., Newhouse, Lanarkshire ML1 5UH, U.K.; European Screening Centre, University of Dundee, Newhouse, Lanarkshire ML1 5UH, U.K., Huggett M; BioAscent Discovery Ltd., Newhouse, Lanarkshire ML1 5UH, U.K.; European Screening Centre, University of Dundee, Newhouse, Lanarkshire ML1 5UH, U.K., Robinson L; BioAscent Discovery Ltd., Newhouse, Lanarkshire ML1 5UH, U.K.; European Screening Centre, University of Dundee, Newhouse, Lanarkshire ML1 5UH, U.K., Gillespie J; BioAscent Discovery Ltd., Newhouse, Lanarkshire ML1 5UH, U.K.; European Screening Centre, University of Dundee, Newhouse, Lanarkshire ML1 5UH, U.K., Rajamanickam M; BioAscent Discovery Ltd., Newhouse, Lanarkshire ML1 5UH, U.K.; European Screening Centre, University of Dundee, Newhouse, Lanarkshire ML1 5UH, U.K., Morrison A; BioAscent Discovery Ltd., Newhouse, Lanarkshire ML1 5UH, U.K.; European Screening Centre, University of Dundee, Newhouse, Lanarkshire ML1 5UH, U.K., McElroy S; BioAscent Discovery Ltd., Newhouse, Lanarkshire ML1 5UH, U.K.; European Screening Centre, University of Dundee, Newhouse, Lanarkshire ML1 5UH, U.K., Tikhonova IG; School of Pharmacy, Medical Biology Centre, Queen's University Belfast, Belfast BT9 7BL, U.K., Milligan G; Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, University of Glasgow, Davidson Building, Glasgow G12 8QQ, U.K., Jamieson AG; School of Chemistry, University of Glasgow, Joseph Black Building, University Avenue, Glasgow G12 8QQ, U.K.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2022 Aug 25; Vol. 65 (16), pp. 11270-11290. Date of Electronic Publication: 2022 Aug 10.
DOI:	10.1021/acs.jmedchem.2c00804
Abstrakt:	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:	MEDLINE
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