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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...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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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. |
format | Online Article Text |
id | pubmed-9234964 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
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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