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
  • 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.