Discovery of 3‑Phenyl Indazole-Based Novel Chemokine-like Receptor 1 Antagonists for the Treatment of Psoriasis

Chemokine-like receptor 1 (CMKLR1)a G protein-coupled
receptorhas
functional roles in the immune system and related diseases, including
psoriasis and metabolic diseases. Psoriasis is a chronic inflammatory
disease characterized by skin redness, scaliness, and itching. In
this study, we sought to develop novel CMKLR1 antagonists by screening
our in-house GPCR-targeting compound library. Moreover, we optimized
a phenylindazole-based hit compound with antagonistic activities and
evaluated its oral pharmacokinetic properties in a murine model. A
structure-based design on the human CMKLR1 homology model identified S-26d as an optimized compound that serves
as a potent and orally available antagonist with a pIC50 value of 7.44 in hCMKLR1-transfected CHO cells.
Furthermore, in the imiquimod-induced psoriasis-like mouse model,
oral administration of S-26d for 1 week
significantly alleviated modified psoriasis area and severity index
scores (severity of erythema, scaliness, skin thickness) compared
with the control group.