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

Labéguère, F. et al. (2020) 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. Journal of Medicinal Chemistry, 63(22), pp. 13526-13545. (doi: 10.1021/acs.jmedchem.0c00272) (PMID:32902984)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jenkins, Mrs Laura and Milligan, Professor Graeme
• Authors: Labéguère, F., Dupont, S., Alvey, L., Soulas, F., Newsome, G., Tirera, A., Quenehen, V., Mai, T. T. T., 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.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Journal of Medicinal Chemistry
• Publisher: American Chemical Society
• ISSN: 0022-2623
• ISSN (Online): 1520-4804
• Published Online: 09 September 2020
• Copyright Holders: Copyright © 2020 American Chemical Society
• First Published: First published in Journal of Medicinal Chemistry 63(22): 13526-13545
• Publisher Policy: Reproduced under a Creative Commons License