Discovery of 9-Cyclopropylethynyl-2-((S)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one (GLPG1205), a Unique GPR84 Negative Allosteric Modulator Undergoing Evaluation in a Phase II Clinical Trial
| Autor: | Graeme Milligan, Luke Jonathan Alvey, Annick Hagers, Thierry Christophe, Emanuelle Wakselman, Luc Nelles, Line Oste, Steve De Vos, Ann Vandevelde, Katja Conrath, Laurent Saniere, Stephen Robert Fletcher, Laura Jenkins, Sandrine Le Tallec, D. Merciris, Pierre Deprez, Roland Blanque, C. Cottereaux, Romain Luc Marie Gosmini, Ellen van der Aar, Cécile da Costa, Sonia Dupont, Thi Thu Trang Mai, Vanessa Quenehen, Labeguere Frederic Gilbert, Philippe Clément-Lacroix, Florilène Soulas, Reginald Brys, Gregory John Robert Newsome, Nele Vandervoort, Amynata Tirera |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Allosteric modulator Drug discovery Antagonist Guanosine Pharmacology 01 natural sciences 0104 chemical sciences 010404 medicinal & biomolecular chemistry 03 medical and health sciences chemistry.chemical_compound chemistry Sulfasalazine Drug Discovery medicine GPR84 Molecular Medicine Potency Receptor 030304 developmental biology medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 63:13526-13545 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | GPR84 is a medium chain free fatty acid-binding G-protein-coupled receptor associated with inflammatory and fibrotic diseases. As the only reported antagonist of GPR84 (PBI-4050) that displays relatively low potency and selectivity, a clear need exists for an improved modulator. Structural optimization of GPR84 antagonist hit 1, identified through high-throughput screening, led to the identification of potent and selective GPR84 inhibitor GLPG1205 (36). Compared with the initial hit, 36 showed improved potency in a guanosine 5′-O-[γ-thio]triphosphate assay, exhibited metabolic stability, and lacked activity against phosphodiesterase-4. This novel pharmacological tool allowed investigation of the therapeutic potential of GPR84 inhibition. At once-daily doses of 3 and 10 mg/kg, GLPG1205 reduced disease activity index score and neutrophil infiltration in a mouse dextran sodium sulfate-induced chronic inflammatory bowel disease model, with efficacy similar to positive-control compound sulfasalazine. The drug discovery steps leading to GLPG1205 identification, currently under phase II clinical investigation, are described herein. |
| Databáze: | OpenAIRE |
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