2. Academic Validation
  3. 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

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

  • J Med Chem. 2020 Nov 25;63(22):13526-13545. doi: 10.1021/acs.jmedchem.0c00272.
Frédéric Labéguère 1,  Sonia Dupont 1,  Luke Alvey 1,  Florilène Soulas 1,  Gregory Newsome 1,  Amynata Tirera 1,  Vanessa Quenehen 1,  Thi Thu Trang Mai 1,  Pierre Deprez 1,  Roland Blanqué 1,  Line Oste 2,  Sandrine Le Tallec 1,  Steve De Vos 2,  Annick Hagers 2,  Ann Vandevelde 2,  Luc Nelles 2,  Nele Vandervoort 2,  Katja Conrath 2,  Thierry Christophe 2,  Ellen van der Aar 2,  Emanuelle Wakselman 1,  Didier Merciris 1,  Céline Cottereaux 1,  Cécile da Costa 1,  Laurent Saniere 1,  Philippe Clement-Lacroix 1,  Laura Jenkins 3,  Graeme Milligan 3,  Stephen Fletcher 2,  Reginald Brys 2,  Romain Gosmini 1
Affiliations

Affiliations

  • 1 Galapagos SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.
  • 2 Galapagos NV, Generaal De Wittelaan L11 A3, 2800 Mechelen, Belgium.
  • 3 Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom.
PMID: 32902984 DOI: 10.1021/acs.jmedchem.0c00272
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.

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