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Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity

[Image: see text] To discover a novel series of potent inhibitors of enteropeptidase, a membrane-bound serine protease localized to the duodenal brush border, 4-guanidinobenzoate derivatives were evaluated with minimal systemic exposure. The 1c docking model enabled the installation of an additional...

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Autores principales: Ikeda, Zenichi, Kakegawa, Keiko, Kikuchi, Fumiaki, Itono, Sachiko, Oki, Hideyuki, Yashiro, Hiroaki, Hiyoshi, Hideyuki, Tsuchimori, Kazue, Hamagami, Kenichi, Watanabe, Masanori, Sasaki, Masako, Ishihara, Youko, Tohyama, Kimio, Kitazaki, Tomoyuki, Maekawa, Tsuyoshi, Sasaki, Minoru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234964/
https://www.ncbi.nlm.nih.gov/pubmed/35686954
http://dx.doi.org/10.1021/acs.jmedchem.2c00463
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author Ikeda, Zenichi
Kakegawa, Keiko
Kikuchi, Fumiaki
Itono, Sachiko
Oki, Hideyuki
Yashiro, Hiroaki
Hiyoshi, Hideyuki
Tsuchimori, Kazue
Hamagami, Kenichi
Watanabe, Masanori
Sasaki, Masako
Ishihara, Youko
Tohyama, Kimio
Kitazaki, Tomoyuki
Maekawa, Tsuyoshi
Sasaki, Minoru
author_facet Ikeda, Zenichi
Kakegawa, Keiko
Kikuchi, Fumiaki
Itono, Sachiko
Oki, Hideyuki
Yashiro, Hiroaki
Hiyoshi, Hideyuki
Tsuchimori, Kazue
Hamagami, Kenichi
Watanabe, Masanori
Sasaki, Masako
Ishihara, Youko
Tohyama, Kimio
Kitazaki, Tomoyuki
Maekawa, Tsuyoshi
Sasaki, Minoru
author_sort Ikeda, Zenichi
collection PubMed
description [Image: see text] To discover a novel series of potent inhibitors of enteropeptidase, a membrane-bound serine protease localized to the duodenal brush border, 4-guanidinobenzoate derivatives were evaluated with minimal systemic exposure. The 1c docking model enabled the installation of an additional carboxylic acid moiety to obtain an extra interaction with enteropeptidase, yielding 2a. The oral administration of 2a significantly elevated the fecal protein output, a pharmacodynamic marker, in diet-induced obese (DIO) mice, whereas subcutaneous administration did not change this parameter. Thus, systemic exposure of 2a was not required for its pharmacological effects. Further optimization focusing on the in vitro IC(50) value and T(1/2), an indicator of dissociation time, followed by enhanced in vivo pharmacological activity based on the ester stability of the compounds, revealed two series of potent enteropeptidase inhibitors, a dihydrobenzofuran analogue ((S)-5b, SCO-792) and phenylisoxazoline (6b), which exhibited potent anti-obesity effects despite their low systemic exposure following their oral administration to DIO rats.
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spelling pubmed-92349642022-06-28 Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity Ikeda, Zenichi Kakegawa, Keiko Kikuchi, Fumiaki Itono, Sachiko Oki, Hideyuki Yashiro, Hiroaki Hiyoshi, Hideyuki Tsuchimori, Kazue Hamagami, Kenichi Watanabe, Masanori Sasaki, Masako Ishihara, Youko Tohyama, Kimio Kitazaki, Tomoyuki Maekawa, Tsuyoshi Sasaki, Minoru J Med Chem [Image: see text] To discover a novel series of potent inhibitors of enteropeptidase, a membrane-bound serine protease localized to the duodenal brush border, 4-guanidinobenzoate derivatives were evaluated with minimal systemic exposure. The 1c docking model enabled the installation of an additional carboxylic acid moiety to obtain an extra interaction with enteropeptidase, yielding 2a. The oral administration of 2a significantly elevated the fecal protein output, a pharmacodynamic marker, in diet-induced obese (DIO) mice, whereas subcutaneous administration did not change this parameter. Thus, systemic exposure of 2a was not required for its pharmacological effects. Further optimization focusing on the in vitro IC(50) value and T(1/2), an indicator of dissociation time, followed by enhanced in vivo pharmacological activity based on the ester stability of the compounds, revealed two series of potent enteropeptidase inhibitors, a dihydrobenzofuran analogue ((S)-5b, SCO-792) and phenylisoxazoline (6b), which exhibited potent anti-obesity effects despite their low systemic exposure following their oral administration to DIO rats. American Chemical Society 2022-06-10 2022-06-23 /pmc/articles/PMC9234964/ /pubmed/35686954 http://dx.doi.org/10.1021/acs.jmedchem.2c00463 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Ikeda, Zenichi
Kakegawa, Keiko
Kikuchi, Fumiaki
Itono, Sachiko
Oki, Hideyuki
Yashiro, Hiroaki
Hiyoshi, Hideyuki
Tsuchimori, Kazue
Hamagami, Kenichi
Watanabe, Masanori
Sasaki, Masako
Ishihara, Youko
Tohyama, Kimio
Kitazaki, Tomoyuki
Maekawa, Tsuyoshi
Sasaki, Minoru
Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity
title Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity
title_full Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity
title_fullStr Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity
title_full_unstemmed Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity
title_short Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity
title_sort design, synthesis, and biological evaluation of a novel series of 4-guanidinobenzoate derivatives as enteropeptidase inhibitors with low systemic exposure for the treatment of obesity
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234964/
https://www.ncbi.nlm.nih.gov/pubmed/35686954
http://dx.doi.org/10.1021/acs.jmedchem.2c00463
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