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

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posted on 2023-10-26, 19:40 authored by Bongki Ko, Yongsoo Jang, Seung-hwa Kwak, Hyun You, Jeong-hyun Kim, Jung-Eun Lee, Hee Dong Park, Soo-Kyung Kim, William A. Goddard, Jung Hyun Han, Yong-Chul Kim
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.

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