GPR84 is a member of the metabolic G protein-coupled receptor family mainly expressed in immune cells and upregulated under inflammatory conditions. It plays an important role in driving chemotaxis of several leukocyte subtypes upon activation by medium chain fatty acid type ligands. In this presentation, the identification of potent dihydropyrimidino-isoquinolinones acting as GPR84 functional antagonists will be described. The set-up of the biological cascade and the optimization of the <i>in vitro</i> potency and ADME/PK properties of the Hit series leading to the identification of GLPG1205 will be addressed. The chemical structure of GLPG1205 will be disclosed. In addition, studies establishing the particular binding mode of GLPG1205 and its close analogues as negative allosteric modulators will be documented. The effect of GLPG1205 on neutrophil and macrophage chemotaxis assays, its efficacy in a chronic mouse colitis model as well as pharmacological data supporting current progression of GLPG1205 in a phase IIa clinical trial in IPF (NCT03725852) will be presented.

Discovery and disclosure of GLPG1205, a first in class GPR84 negative allosteric modulator in phase II clinical trial

2019 Fall National Meeting

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