posted on 2023-12-26, 09:29authored byPinqi Wang, Arun Raja, Vincent B. Luscombe, Carole J. R. Bataille, Daniel Lucy, Vanessa V. Rogga, David R. Greaves, 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
signaling 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 signaling 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 signaling bias, and an appropriate in vivo pharmacokinetic profile that will allow investigation of GPR84 biased
agonist activity in vivo.