Discovery of 9-Cyclopropylethynyl-2-((<i>S</i>)-1-[1,4]dioxan-2-ylmethoxy)-6,7-dihydropyrimido[6,1-<i>a</i>]isoquinolin-4-one (GLPG1205), a Unique GPR84 Negative Allosteric Modulator Undergoing Evaluation in a Phase II Clinical Trial
Frédéric Labéguère, Sonia Dupont, Luke J. Alvey, Florilène Soulas, Gregory Newsome, Amynata Tirera, Vanessa Quénéhen, Thi Thu Trang, Pierre Deprez, Roland Blanqué, Line Oste, Sandrine Le Tallec, Steve De Vos, Annick Hagers, Ann Vandevelde, L Nelles, Nele Vandervoort, Katja Conrath, Thierry Christophe, Ellen van der Aar, Emanuelle Wakselman, Didier Merciris, C. Cottereaux, Cécile da Costa, Laurent Sanière, Philippe Clément-Lacroix, Laura Jenkins, Graeme Milligan, Stephen R. Fletcher, Reginald Brys, Romain Gosmini
Abstract
-[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.