Publications
Development of Highly Potent, G-Protein Pathway Biased, Selective, and Orally Bioavailable GPR84 Agonists
Pinqi Wang, Arun Raja, Vincent B. Luscombe, Carole J. R. Bataille, Daniel Lucy, Vanessa V. Rogga, David R. Greaves, and Angela J. Russell
Orphan G-protein-coupled receptor 84 (GPR84) is a receptor that has been linked to cancer, inflammatory, and fibrotic diseases. We have reported DL-175 as a biased agonist at GPR84 which showed differential signalling via Gαi/cAMP and β-arrestin, but which is rapidly metabolized. Herein, we describe an optimization of DL-175 through a systematic structure–activity relationship (SAR) analysis. This reveals that the replacement of the naphthalene group improved metabolic stability and the addition of a 5-hydroxy substituent to the pyridine N-oxide group, yielding compounds 68 (OX04528) and 69 (OX04529), enhanced the potency for cAMP signalling by 3 orders of magnitude to low picomolar values. Neither compound showed detectable effects on β-arrestin recruitment up to 80 μM. Thus, the new GPR84 agonists 68 and 69 displayed excellent potency, high G-protein signalling bias, and an appropriate in vivo pharmacokinetic profile that will allow investigation of GPR84 biased agonist activity in vivo.
