Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.
Bioorg Med Chem Lett. 2023 Oct 1;94:129461. doi: 10.1016/j.bmcl.2023.129461. Epub 2023 Aug 29.
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.
色氨酸羟化酶 1（TPH1）已成为治疗肥胖症和脂肪肝等代谢性疾病的靶点。本文合成了一系列黄嘌呤衍生物，并对其 TPH1 抑制活性进行了评价。在所合成的化合物中，化合物 40 表现出良好的体外活性和肝微粒体稳定性。对接研究表明，化合物 40 通过涉及黄嘌呤骨架、咪唑噻唑环和含羟基苯乙酮部分的关键分子间相互作用，与 TPH1 更好地结合。此外，化合物 40 能有效抑制 3T3-L1 脂肪细胞的分化。
