1. Academic Validation
  2. Discovery of a novel BLT2 antagonist for the treatment of inflammatory airway diseases

Discovery of a novel BLT2 antagonist for the treatment of inflammatory airway diseases

  • Eur J Med Chem. 2023 Oct 7:261:115864. doi: 10.1016/j.ejmech.2023.115864.
Hyejun Park 1 Dipesh S Harmalkar 2 Jun-Dong Wei 3 Seunghan Sun 1 Jinsun Kwon 1 Chang Hoon Lee 4 Jae Geun Song 4 Jin-Mi Park 5 Jae-Won Lee 5 Kyung-Seop Ahn 5 Hyo-Kyung Han 4 Jae-Hong Kim 1 Kyeong Lee 6 Yongseok Choi 7
Affiliations

Affiliations

  • 1 College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea.
  • 2 College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea; College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea; Department of Chemistry, Government College of Arts, Science, and Commerce, Sanquelim, Goa, 403505, India.
  • 3 Department of Basic Medical Science, Medical College, Taizhou University, Taizhou, China.
  • 4 College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea.
  • 5 Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Chungcheongbuk-do, Cheongju, 28116, Republic of Korea.
  • 6 College of Pharmacy, Dongguk University-Seoul, Goyang, 10326, Republic of Korea. Electronic address: kaylee@dongguk.edu.
  • 7 College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea. Electronic address: ychoi@korea.ac.kr.
Abstract

Leukotriene B4 (LTB4) is a potent chemoattractant that can recruit and activate immune cells such as neutrophils, eosinophils, and monocytes to sites of inflammation. Excessive production of LTB4 has been linked to acute and chronic inflammatory diseases, including asthma, rheumatoid arthritis, and psoriasis. Inhibiting the binding of LTB4 to its receptors, BLT1 and BLT2, is a potential strategy for treating these conditions. While several BLT1 antagonists have been developed for clinical trials, most have failed due to efficacy and safety issues. Therefore, discovering selective BLT2 antagonists could improve our understanding of the distinct functions of BLT1 and BLT2 receptors and their pharmacological implications. In this study, we aimed to discover novel BLT2 antagonists by synthesizing a series of biphenyl analogues based on a BLT2 selective agonist, CAY10583. Among the synthesized compounds, 15b was found to selectively inhibit the chemotaxis of CHO-BLT2 cells with an IC50 value of 224 nM without inhibiting the chemotaxis of CHO-BLT1 cells. 15b also inhibited the binding of LTB4 and BLT2 with a Ki value of 132 nM. Furthermore, 15b had good metabolic stability in liver microsomes and moderate bioavailability (F = 34%) in in vivo PK studies. 15b also showed in vivo efficacy in a mouse model of asthma, reducing airway hyperresponsiveness by 59% and decreasing Th2 cytokines by up to 46%. Our study provides a promising lead for the development of selective BLT2 antagonists as potential therapeutics for inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease.

Keywords

Asthma; BLT2 antagonist; Chemotaxis; Inflammatory airway disease; Leukotriene B(4) (LTB(4)); Leukotriene B(4) receptor 2 (BLT2); Selectivity.

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