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  3. Synthesis and biological evaluation of xanthine derivatives with phenacyl group as tryptophan hydroxylase 1 (TPH1) inhibitors for obesity and fatty liver disease

Synthesis and biological evaluation of xanthine derivatives with phenacyl group as tryptophan hydroxylase 1 (TPH1) inhibitors for obesity and fatty liver disease

  • Bioorg Med Chem Lett. 2023 Oct 1:94:129461. doi: 10.1016/j.bmcl.2023.129461.
Jihyeon Yoon 1,  Won-Il Choi 2,  Saravanan Parameswaran 3,  Gwi Bin Lee 1,  Byeong Wook Choi 1,  Pyeongkeun Kim 1,  Dae-Seop Shin 4,  Ha Neul Jeong 5,  Seung Mi Lee 6,  Chang Joo Oh 6,  Jae-Han Jeon 7,  In-Kyu Lee 8,  Myung Ae Bae 9,  Hail Kim 10,  Jin Hee Ahn 11
Affiliations

Affiliations

  • 1 Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
  • 2 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
  • 3 Department of Biotechnology & Bioinformatics, JSS Academy of Higher Education and Research, Mysuru 570015, India.
  • 4 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.
  • 5 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea; Department of Medical Chemistry and Pharmacology, University of Science & Technology, Daejeon, 34113, Republic of Korea.
  • 6 Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea.
  • 7 Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea.
  • 8 Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.
  • 9 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea; Department of Medical Chemistry and Pharmacology, University of Science & Technology, Daejeon, 34113, Republic of Korea. Electronic address: [email protected].
  • 10 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. Electronic address: [email protected].
  • 11 Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea; JD Bioscience, 208 Cheomdan-dwagiro, Buk-gu, Gwangju 61005, Republic of Korea. Electronic address: [email protected].
PMID: 37652099 DOI: 10.1016/j.bmcl.2023.129461
Abstract

Tryptophan Hydroxylase 1 (TPH1) has emerged as a target for the treatment of metabolic diseases including obesity and fatty liver disease. A series of xanthine derivatives were synthesized and evaluated for their TPH1 inhibition. Among the synthesized compounds, compound 40 showed good in vitro activity and liver microsomal stability. Docking studies revealed that compound 40 showed better binding to TPH1 via key intermolecular interactions involving the xanthine scaffold, imidazo-thiazolyl ring, and hydroxyl-containing phenacyl moiety. In addition, compound 40 effectively suppressed the adipocyte differentiation of 3 T3-L1 cells.

Keywords

Fatty liver; Obesity; TPH inhibitor; Xanthine.

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