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

  • J Med Chem. 2023 Oct 26. doi: 10.1021/acs.jmedchem.3c01011.
Bongki Ko  1 ,  Yongsoo Jang  1 ,  Seung-Hwa Kwak  1 ,  Hyun You  1 ,  Jeong-Hyun Kim  1 ,  Jung-Eun Lee  1 ,  Hee Dong Park  2 ,  Soo-Kyung Kim  3 ,  William A Goddard 3rd  3 ,  Jung Hyun Han  1  4 ,  Yong-Chul Kim  1  5
Affiliations
  • 1. School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea.
  • 2. Innovo Therapeutics Inc., Daeduck Biz Center C-313, 17 Techno 4-ro, Yuseong-gu, Daejeon 34013, Republic of Korea.
  • 3. Materials and Process Simulation Center, California Institute of Technology, Pasadena, California 91125, United States.
  • 4. Department of Dermatology, Saint John of God Hospital, Gwangju 61245, Republic of Korea.
  • 5. Center for AI-Applied High Efficiency Drug Discovery (AHEDD), Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea.
PMID: 37883692 DOI: 10.1021/acs.jmedchem.3c01011
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.

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