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

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 <b>1</b>, identified through high-throughput screening, led to the identification of potent and selective GPR84 inhibitor GLPG1205 (<b>36</b>). Compared with the initial hit, <b>36</b> showed improved potency in a guanosine 5'-<i>O</i>-[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.