2. Academic Validation
  3. Discovery of a novel series of medium-sized cyclic enteropeptidase inhibitors

Discovery of a novel series of medium-sized cyclic enteropeptidase inhibitors

  • Bioorg Med Chem. 2023 Oct 1;93:117462. doi: 10.1016/j.bmc.2023.117462.
Fumiaki Kikuchi 1,  Zenichi Ikeda 2,  Keiko Kakegawa 2,  Youichi Nishikawa 2,  Shigekazu Sasaki 2,  Koichiro Fukuda 2,  Kazuaki Takami 2,  Yoshihiro Banno 2,  Hitoaki Nishikawa 2,  Naohiro Taya 2,  Takashi Nakahata 2,  Sachiko Itono 2,  Hiroaki Yashiro 2,  Kazue Tsuchimori 2,  Hideyuki Hiyoshi 2,  Masako Sasaki 2,  Kimio Tohyama 2,  Kouta Matsumiya 2,  Youko Ishihara 3,  Tetsuji Kawamoto 2,  Masahiro Kamaura 2,  Masanori Watanabe 2,  Tomoyuki Kitazaki 2,  Tsuyoshi Maekawa 2,  Minoru Sasaki 4
Affiliations

Affiliations

  • 1 Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: [email protected].
  • 2 Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • 3 Pharmaceutical Sciences, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
  • 4 Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: [email protected].
PMID: 37683572 DOI: 10.1016/j.bmc.2023.117462
Abstract

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.

Keywords

Enteropeptidase inhibitor; Lactone; Low systemic exposure; Obesity.

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