Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Korea.
JD Bioscience, 208 beon-gil, Cheomdangwagi-ro, Buk-gu, Gwangju 61005, Korea.
Molecules. 2022 May 25;27(11):3417. doi: 10.3390/molecules27113417.
Serotonin (5-hydroxytryptophan) is a hormone that regulates emotions in the central nervous system. However, serotonin in the peripheral system is associated with obesity and fatty liver disease. Because serotonin cannot cross the blood-brain barrier (BBB), we focused on identifying new tryptophan hydroxylase type I (TPH1) inhibitors that act only in peripheral tissues for treating obesity and fatty liver disease without affecting the central nervous system. Structural optimization inspired by -chlorophenylalanine (pCPA) resulted in the identification of a series of oxyphenylalanine and heterocyclic phenylalanine derivatives as TPH1 inhibitors. Among these compounds, compound with an value of 37 nM was the most active in vitro. Additionally, compound showed good liver microsomal stability and did not significantly inhibit CYP and Herg. Furthermore, this TPH1 inhibitor was able to actively interact with the peripheral system without penetrating the BBB. Compound and its prodrug reduced body weight gain in mammals and decreased in vivo fat accumulation.
血清素（5-羟色氨酸）是一种调节中枢神经系统情绪的激素。然而，外周系统中的血清素与肥胖和脂肪肝疾病有关。由于血清素不能穿过血脑屏障（BBB），我们专注于鉴定新的仅在外周组织中起作用的色氨酸羟化酶 1（TPH1）抑制剂，用于治疗肥胖和脂肪肝疾病，而不影响中枢神经系统。受 -氯苯丙氨酸（pCPA）启发的结构优化导致发现了一系列氧代苯丙氨酸和杂环苯丙氨酸衍生物作为 TPH1 抑制剂。在这些化合物中，化合物 具有 37nM 的 值，体外活性最高。此外，化合物 表现出良好的肝微粒体稳定性，并且对 CYP 和 Herg 没有明显的抑制作用。此外，这种 TPH1 抑制剂能够主动与外周系统相互作用而不穿透 BBB。化合物 和其前药可减少哺乳动物的体重增加并减少体内脂肪堆积。
