1. 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.
- Author
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Labéguère F, Dupont S, Alvey L, Soulas F, Newsome G, Tirera A, Quenehen V, Mai TTT, Deprez P, Blanqué R, Oste L, Le Tallec S, De Vos S, Hagers A, Vandevelde A, Nelles L, Vandervoort N, Conrath K, Christophe T, van der Aar E, Wakselman E, Merciris D, Cottereaux C, da Costa C, Saniere L, Clement-Lacroix P, Jenkins L, Milligan G, Fletcher S, Brys R, and Gosmini R
- Subjects
- Acetates chemistry, Acetates pharmacology, Allosteric Regulation drug effects, Allosteric Regulation physiology, Animals, Caco-2 Cells, Cells, Cultured, Dogs, Drug Evaluation, Preclinical methods, Female, HEK293 Cells, Humans, Male, Mice, Mice, Inbred BALB C, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Rats, Rats, Sprague-Dawley, Drug Discovery methods, Receptors, G-Protein-Coupled antagonists & inhibitors, Receptors, G-Protein-Coupled metabolism
- Abstract
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.
- Published
- 2020
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