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.