Discovery of intestinal targeted TGR5 agonists for the treatment of type 2 diabetes

Hongliang Duan; Mengmeng Ning; Qingan Zou; Yangliang Ye; Ying Feng; Lina Zhang; Ying Leng; Jianhua Shen

doi:10.1021/jm500829b

Discovery of intestinal targeted TGR5 agonists for the treatment of type 2 diabetes

Hongliang Duan, Mengmeng Ning, Qingan Zou, Yangliang Ye, Ying Feng, Lina Zhang, Ying Leng, Jianhua Shen

CAS - Shanghai Institute of Materia Medica

研究成果: Article › 同行評審

80 引文斯高帕斯（Scopus）

摘要

Activation of TGR5 stimulates intestinal glucagon-like peptide-1 (GLP-1) release, but activation of the receptors in gallbladder and heart has been shown to cause severe on-target side effects. A series of low-absorbed TGR5 agonists was prepared by modifying compound 2 with polar functional groups to limit systemic exposure and specifically activate TGR5 in the intestine. Compound 15c, with a molecular weight of 1401, a PSA value of 223 Å², and low permeability on Caco-2 cells, exhibited satisfactory potency both in vitro and in vivo. Low levels of 15c were detected in blood, bile, and gallbladder tissue, and gallbladder-related side effects were substantially decreased compared to the absorbed small-molecule TGR5 agonist 2.

原文	English
頁（從 - 到）	3315-3328
頁數	14
期刊	Journal of Medicinal Chemistry
卷	58
發行號	8
DOIs	https://doi.org/10.1021/jm500829b
出版狀態	Published - 23 4月 2015
對外發佈	是

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title = "Discovery of intestinal targeted TGR5 agonists for the treatment of type 2 diabetes",

abstract = "Activation of TGR5 stimulates intestinal glucagon-like peptide-1 (GLP-1) release, but activation of the receptors in gallbladder and heart has been shown to cause severe on-target side effects. A series of low-absorbed TGR5 agonists was prepared by modifying compound 2 with polar functional groups to limit systemic exposure and specifically activate TGR5 in the intestine. Compound 15c, with a molecular weight of 1401, a PSA value of 223 {\AA}2, and low permeability on Caco-2 cells, exhibited satisfactory potency both in vitro and in vivo. Low levels of 15c were detected in blood, bile, and gallbladder tissue, and gallbladder-related side effects were substantially decreased compared to the absorbed small-molecule TGR5 agonist 2.",

author = "Hongliang Duan and Mengmeng Ning and Qingan Zou and Yangliang Ye and Ying Feng and Lina Zhang and Ying Leng and Jianhua Shen",

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T1 - Discovery of intestinal targeted TGR5 agonists for the treatment of type 2 diabetes

AU - Duan, Hongliang

AU - Ning, Mengmeng

AU - Zou, Qingan

AU - Ye, Yangliang

AU - Feng, Ying

AU - Zhang, Lina

AU - Leng, Ying

AU - Shen, Jianhua

PY - 2015/4/23

Y1 - 2015/4/23

N2 - Activation of TGR5 stimulates intestinal glucagon-like peptide-1 (GLP-1) release, but activation of the receptors in gallbladder and heart has been shown to cause severe on-target side effects. A series of low-absorbed TGR5 agonists was prepared by modifying compound 2 with polar functional groups to limit systemic exposure and specifically activate TGR5 in the intestine. Compound 15c, with a molecular weight of 1401, a PSA value of 223 Å2, and low permeability on Caco-2 cells, exhibited satisfactory potency both in vitro and in vivo. Low levels of 15c were detected in blood, bile, and gallbladder tissue, and gallbladder-related side effects were substantially decreased compared to the absorbed small-molecule TGR5 agonist 2.

AB - Activation of TGR5 stimulates intestinal glucagon-like peptide-1 (GLP-1) release, but activation of the receptors in gallbladder and heart has been shown to cause severe on-target side effects. A series of low-absorbed TGR5 agonists was prepared by modifying compound 2 with polar functional groups to limit systemic exposure and specifically activate TGR5 in the intestine. Compound 15c, with a molecular weight of 1401, a PSA value of 223 Å2, and low permeability on Caco-2 cells, exhibited satisfactory potency both in vitro and in vivo. Low levels of 15c were detected in blood, bile, and gallbladder tissue, and gallbladder-related side effects were substantially decreased compared to the absorbed small-molecule TGR5 agonist 2.

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Discovery of intestinal targeted TGR5 agonists for the treatment of type 2 diabetes

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