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

Authors

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

Published in

Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents. Mar 31, 2026. Epub Mar 31, 2026.

Abstract

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.

PMID:
42446534
Bibliographic data and abstract were imported from PubMed on 14 Aug 2026.

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