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<p>In this study, we discovered and optimized a novel series of <span>l</span>-type amino acid transporter 1 (LAT1)-selective inhibitors. Starting from compound <b>1</b>, efforts to explore the structure–activity relationship and optimize selectivity over <span>l</span>-type amino acid transporter 2 (LAT2) revealed the importance of the orientation of the terminal aromatic ring and led to the highly potent and LAT1-selective 2-phenoxy-substituted compound <b>19</b>. Pharmacokinetic studies of <b>19</b> demonstrated that it is orally bioavailable (10 mg/kg, p.o., mouse, AUC:2354 ng·h/mL). Further optimization of the aromatic ring improved its metabolic stability and resulted in highly LAT1-selective and orally bioavailable (10 mg/kg, p.o., mouse, AUC:3449 ng·h/mL) compound <b>26</b>. This series of compounds should be useful for research on LAT1 inhibitors.</p><p></p>

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Discovery of 3-(N-phenylsulfamoyl)-l-phenylalanine derivatives as novel and orally available LAT1-selective inhibitors

  • 期刊论文

  • 发表日期：

    2026年3月31日

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  • Shuhei Uesugi,
  • Tomoyuki Tsunemi,
  • Hidenobu Murafuji,
  • Kumiko Kadoshima-Yamaoka,
  • Masao Murakawa,
  • Naoyuki Makita,
  • Urara Tomita,
  • Yukiko Doke,
  • Hiroshi Yukiura,
  • Makoto Koyama,
  • Yasuhiro Hayashi,
  • Kyoko Yamashiro,
  • Kazunori Yoshikiyo,
  • Toshiki Tabata,
  • Hiroshi Maruoka

摘要

In this study, we discovered and optimized a novel series of l-type amino acid transporter 1 (LAT1)-selective inhibitors. Starting from compound 1, efforts to explore the structure–activity relationship and optimize selectivity over l-type amino acid transporter 2 (LAT2) revealed the importance of the orientation of the terminal aromatic ring and led to the highly potent and LAT1-selective 2-phenoxy-substituted compound 19. Pharmacokinetic studies of 19 demonstrated that it is orally bioavailable (10 mg/kg, p.o., mouse, AUC:2354 ng·h/mL). Further optimization of the aromatic ring improved its metabolic stability and resulted in highly LAT1-selective and orally bioavailable (10 mg/kg, p.o., mouse, AUC:3449 ng·h/mL) compound 26. This series of compounds should be useful for research on LAT1 inhibitors.