Bioorganic & medicinal chemistry · 2023
Discovery of a novel series of medium-sized cyclic enteropeptidase inhibitors.
СтатьяНазвание и аннотация: Перевод в очереди
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Kikuchi Fumiaki, Ikeda Zenichi, Kakegawa Keiko, Nishikawa Youichi, Sasaki Shigekazu, Fukuda Koichiro, Takami Kazuaki, Banno Yoshihiro, Nishikawa Hitoaki, Taya Naohiro, Nakahata Takashi, Itono Sachiko, Yashiro Hiroaki, Tsuchimori Kazue, Hiyoshi Hideyuki, Sasaki Masako, Tohyama Kimio, Matsumiya Kouta, Ishihara Youko, Kawamoto Tetsuji, Kamaura Masahiro, Watanabe Masanori, Kitazaki Tomoyuki, Maekawa Tsuyoshi, Sasaki Minoru
Аннотация
Enteropeptidase is located in the duodenum that involved in intestinal protein digestion. We have reported enteropeptidase inhibitors with low systemic exposure. The aim of this study was to discover novel enteropeptidase inhibitors showing more potent in vivo efficacy while retaining low systemic exposure. Inhibitory mechanism-based drug design led us to cyclize ester 2 to medium-sized lactones, showing potent enteropeptidase inhibitory activity and improving the ester stability, thus increasing fecal protein output in vivo. Optimization on the linker between two benzene rings resulted in discovery of ether lactone 6b, exhibiting further enhanced enteropeptidase inhibitory activity and long duration of inhibitory state. Oral administration of 6b in mice significantly elevated fecal protein output compared with the lead 2. In addition, 6b showed low systemic exposure along with low intestinal absorption. Furthermore, we identified the 10-membered lactonization method for scale-up synthesis of 6b, which does not require high-dilution conditions.