Design of G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) soft drugs with reduced gallbladder-filling effects
The G-protein-coupled bile acid receptor TGR5 agonists were widely developed in type 2 diabetes and gastrointestinal disorders, but were also full of challenges, due to the systemic on-targeted side effects, especially the gallbladder-filling effects. Here, to circumvent these risks, several TGR5 ag...
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| Veröffentlicht in: | European journal of medicinal chemistry 2020-10, Vol.203, p.112619-112619, Article 112619 |
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| container_title | European journal of medicinal chemistry |
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| creator | Han, Fanghui Ning, Mengmeng Cao, Hua Ye, Yangliang Feng, Ying Leng, Ying Shen, Jianhua |
| description | The G-protein-coupled bile acid receptor TGR5 agonists were widely developed in type 2 diabetes and gastrointestinal disorders, but were also full of challenges, due to the systemic on-targeted side effects, especially the gallbladder-filling effects. Here, to circumvent these risks, several TGR5 agonists with soft-drug designation had been designed and synthesized with the properties of rapid metabolized after drug effect. Among them, compound 19 showed negligible systemic exposure and favorable gallbladder safety on a 3-day continuous administration, providing a novel strategy for developing TGR5 agonists.
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•Soft-drug TGR5 agonists were first designed, synthesized and evaluated.•19 could be rapidly metabolized into inactive metabolite after exerting efficacy.•19 showed negligible systemic exposure and favorable gallbladder safety.•Soft drug strategy is a novel strategy for the development of TGR5 agonists. |
| doi_str_mv | 10.1016/j.ejmech.2020.112619 |
| format | Article |
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[Display omitted]
•Soft-drug TGR5 agonists were first designed, synthesized and evaluated.•19 could be rapidly metabolized into inactive metabolite after exerting efficacy.•19 showed negligible systemic exposure and favorable gallbladder safety.•Soft drug strategy is a novel strategy for the development of TGR5 agonists.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2020.112619</identifier><identifier>PMID: 32682201</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Animals ; Carboxylic ester ; Drug Design ; Gallbladder - drug effects ; Gallbladder - metabolism ; Gallbladder-filling effects ; GLP-1 ; Humans ; Male ; Mice ; Pyridines - chemical synthesis ; Pyridines - chemistry ; Pyridines - metabolism ; Pyridines - pharmacology ; Rapid metabolism ; Receptors, G-Protein-Coupled - agonists ; Receptors, G-Protein-Coupled - metabolism ; Risk ; Soft drug ; TGR5</subject><ispartof>European journal of medicinal chemistry, 2020-10, Vol.203, p.112619-112619, Article 112619</ispartof><rights>2020 Elsevier Masson SAS</rights><rights>Copyright © 2020 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-302f330b9b3e2330e16d6e021096f609f98de43154b909a49e323b6d8d099eb3</citedby><cites>FETCH-LOGICAL-c362t-302f330b9b3e2330e16d6e021096f609f98de43154b909a49e323b6d8d099eb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejmech.2020.112619$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32682201$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Han, Fanghui</creatorcontrib><creatorcontrib>Ning, Mengmeng</creatorcontrib><creatorcontrib>Cao, Hua</creatorcontrib><creatorcontrib>Ye, Yangliang</creatorcontrib><creatorcontrib>Feng, Ying</creatorcontrib><creatorcontrib>Leng, Ying</creatorcontrib><creatorcontrib>Shen, Jianhua</creatorcontrib><title>Design of G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) soft drugs with reduced gallbladder-filling effects</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>The G-protein-coupled bile acid receptor TGR5 agonists were widely developed in type 2 diabetes and gastrointestinal disorders, but were also full of challenges, due to the systemic on-targeted side effects, especially the gallbladder-filling effects. Here, to circumvent these risks, several TGR5 agonists with soft-drug designation had been designed and synthesized with the properties of rapid metabolized after drug effect. Among them, compound 19 showed negligible systemic exposure and favorable gallbladder safety on a 3-day continuous administration, providing a novel strategy for developing TGR5 agonists.
[Display omitted]
•Soft-drug TGR5 agonists were first designed, synthesized and evaluated.•19 could be rapidly metabolized into inactive metabolite after exerting efficacy.•19 showed negligible systemic exposure and favorable gallbladder safety.•Soft drug strategy is a novel strategy for the development of TGR5 agonists.</description><subject>Animals</subject><subject>Carboxylic ester</subject><subject>Drug Design</subject><subject>Gallbladder - drug effects</subject><subject>Gallbladder - metabolism</subject><subject>Gallbladder-filling effects</subject><subject>GLP-1</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - metabolism</subject><subject>Pyridines - pharmacology</subject><subject>Rapid metabolism</subject><subject>Receptors, G-Protein-Coupled - agonists</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Risk</subject><subject>Soft drug</subject><subject>TGR5</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFq3DAQhkVJabZJ36AEHROot6ORrawugSRtt4VAQ9i7sKXRRovW3kh2S96-Ck577GmG4ftnmI-xjwKWAoT6vFvSbk_2cYmAZSRQCf2GLcSlWlUSm_qILQBRVg3K-pi9z3kHAI0CeMeOJaoVIogFy18oh23PB8_X1SENI4W-ssN0iOR4FyLx1gbHE1k6jEPigp-v72-uH8Qnvlk_NBc8D37kLk3bzH-H8bGQbrIlu21j7GLrHKXKhxhDv-XkPdkxn7K3vo2ZPrzWE7b59nVz-726-7n-cXt9V1mpcKwkoJcSOt1JwtKQUE4RoACtvALt9cpRLUVTdxp0W2uSKDvlVg60pk6esPN5bXnraaI8mn3IlmJsexqmbLDGWmshL5uC1jNq05BzIm8OKezb9GwEmBfbZmdm2-bFtpltl9jZ64Wp25P7F_qrtwBXM0DlzV-Bksk2UF_8hGJ0NG4I_7_wBzilj-Q</recordid><startdate>20201001</startdate><enddate>20201001</enddate><creator>Han, Fanghui</creator><creator>Ning, Mengmeng</creator><creator>Cao, Hua</creator><creator>Ye, Yangliang</creator><creator>Feng, Ying</creator><creator>Leng, Ying</creator><creator>Shen, Jianhua</creator><general>Elsevier Masson SAS</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20201001</creationdate><title>Design of G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) soft drugs with reduced gallbladder-filling effects</title><author>Han, Fanghui ; Ning, Mengmeng ; Cao, Hua ; Ye, Yangliang ; Feng, Ying ; Leng, Ying ; Shen, Jianhua</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-302f330b9b3e2330e16d6e021096f609f98de43154b909a49e323b6d8d099eb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Carboxylic ester</topic><topic>Drug Design</topic><topic>Gallbladder - drug effects</topic><topic>Gallbladder - metabolism</topic><topic>Gallbladder-filling effects</topic><topic>GLP-1</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - metabolism</topic><topic>Pyridines - pharmacology</topic><topic>Rapid metabolism</topic><topic>Receptors, G-Protein-Coupled - agonists</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Risk</topic><topic>Soft drug</topic><topic>TGR5</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Han, Fanghui</creatorcontrib><creatorcontrib>Ning, Mengmeng</creatorcontrib><creatorcontrib>Cao, Hua</creatorcontrib><creatorcontrib>Ye, Yangliang</creatorcontrib><creatorcontrib>Feng, Ying</creatorcontrib><creatorcontrib>Leng, Ying</creatorcontrib><creatorcontrib>Shen, Jianhua</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Han, Fanghui</au><au>Ning, Mengmeng</au><au>Cao, Hua</au><au>Ye, Yangliang</au><au>Feng, Ying</au><au>Leng, Ying</au><au>Shen, Jianhua</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design of G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) soft drugs with reduced gallbladder-filling effects</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2020-10-01</date><risdate>2020</risdate><volume>203</volume><spage>112619</spage><epage>112619</epage><pages>112619-112619</pages><artnum>112619</artnum><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>The G-protein-coupled bile acid receptor TGR5 agonists were widely developed in type 2 diabetes and gastrointestinal disorders, but were also full of challenges, due to the systemic on-targeted side effects, especially the gallbladder-filling effects. Here, to circumvent these risks, several TGR5 agonists with soft-drug designation had been designed and synthesized with the properties of rapid metabolized after drug effect. Among them, compound 19 showed negligible systemic exposure and favorable gallbladder safety on a 3-day continuous administration, providing a novel strategy for developing TGR5 agonists.
[Display omitted]
•Soft-drug TGR5 agonists were first designed, synthesized and evaluated.•19 could be rapidly metabolized into inactive metabolite after exerting efficacy.•19 showed negligible systemic exposure and favorable gallbladder safety.•Soft drug strategy is a novel strategy for the development of TGR5 agonists.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>32682201</pmid><doi>10.1016/j.ejmech.2020.112619</doi><tpages>1</tpages></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Carboxylic ester Drug Design Gallbladder - drug effects Gallbladder - metabolism Gallbladder-filling effects GLP-1 Humans Male Mice Pyridines - chemical synthesis Pyridines - chemistry Pyridines - metabolism Pyridines - pharmacology Rapid metabolism Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - metabolism Risk Soft drug TGR5 |
| title | Design of G-protein-coupled bile acid receptor 1 (GPBAR1, TGR5) soft drugs with reduced gallbladder-filling effects |
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