Discovery of 3-Phenyl Indazole-Based Novel Chemokine-like Receptor 1 Antagonists for the Treatment of Psoriasis
Bongki Ko, Yongsoo Jang, Seung-hwa Kwak, Hyun You, Jeong-hyun Kim, Jung-Eun Lee, Hee Dong Park, Soo-Kyung Kim, William A. Goddard III, Jung Hyun Han, Yong-Chul Kim
Abstract
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.
Group Members
Ko, B., Jang, Y., Kwak, S., You, H., Kim, J., Lee, J., Park, H. D., Kim, S., III, W. A. G., Han, J. H., & Kim, Y. (2023). Discovery of 3-Phenyl Indazole-Based Novel Chemokine-like Receptor 1 Antagonists for the Treatment of Psoriasis. *Journal of Medicinal Chemistry*, *66*(21), 14564-14582. https://doi.org/10.1021/acs.jmedchem.3c01011