Optimization of the first small-molecule relaxin/insulin-like family peptide receptor (RXFP1) agonists: Activation results in an antifibrotic gene expression profile
A dose responsive quantitative high throughput screen (qHTS) of >350,000 compounds against a human relaxin/insulin-like family peptide receptor (RXFP1) transfected HEK293 cell line identified 2-acetamido-N-phenylbenzamides 1 and 3 with modest agonist activity. An extensive structure-activity stud...
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| Veröffentlicht in: | European journal of medicinal chemistry 2018-08, Vol.156, p.79-92 |
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| container_title | European journal of medicinal chemistry |
| container_volume | 156 |
| creator | Wilson, Kenneth J. Xiao, Jingbo Chen, Catherine Z. Huang, Zaohua Agoulnik, Irina U. Ferrer, Marc Southall, Noel Hu, Xin Zheng, Wei Xu, Xin Wang, Amy Myhr, Courtney Barnaeva, Elena George, Emmett R. Agoulnik, Alexander I. Marugan, Juan J. |
| description | A dose responsive quantitative high throughput screen (qHTS) of >350,000 compounds against a human relaxin/insulin-like family peptide receptor (RXFP1) transfected HEK293 cell line identified 2-acetamido-N-phenylbenzamides 1 and 3 with modest agonist activity. An extensive structure-activity study has been undertaken to optimize the potency, efficacy, and physical properties of the series, resulting in the identification of compound 65 (ML-290), which has excellent in vivo PK properties with high levels of systemic exposure. This series, exemplified by 65, has produced first-in-class small-molecule agonists of RXFP1 and is a potent activator of anti-fibrotic genes.
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•A high throughput screening campaign identified the first small molecule relaxin peptide hormone receptor agonists.•An extensive medicinal chemistry effort produced an optimized, potent lead compound.•Pharmokinetic studies show good compound bioavailability in mice with no observed toxicity.•The lead compound displays an antifibrotic gene expression profile in activated human hepatic stellate cells. |
| doi_str_mv | 10.1016/j.ejmech.2018.06.008 |
| format | Article |
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[Display omitted]
•A high throughput screening campaign identified the first small molecule relaxin peptide hormone receptor agonists.•An extensive medicinal chemistry effort produced an optimized, potent lead compound.•Pharmokinetic studies show good compound bioavailability in mice with no observed toxicity.•The lead compound displays an antifibrotic gene expression profile in activated human hepatic stellate cells.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2018.06.008</identifier><identifier>PMID: 30006176</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>2-Acetamido-N-Phenylbenzamide ; Animals ; Antifibrotic ; Benzamides - chemistry ; Benzamides - pharmacokinetics ; Benzamides - pharmacology ; Cell Line ; G-protein coupled receptor ; HEK293 Cells ; Hepatic Stellate Cells - drug effects ; Hepatic Stellate Cells - metabolism ; Hepatic Stellate Cells - pathology ; Humans ; Liver Cirrhosis - drug therapy ; Liver Cirrhosis - genetics ; Liver Cirrhosis - metabolism ; Liver Cirrhosis - pathology ; Mice, Inbred C57BL ; Models, Molecular ; Receptors, G-Protein-Coupled - agonists ; Receptors, G-Protein-Coupled - metabolism ; Receptors, Peptide - agonists ; Receptors, Peptide - metabolism ; Relaxin ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - pharmacokinetics ; Small Molecule Libraries - pharmacology ; Transcriptome - drug effects</subject><ispartof>European journal of medicinal chemistry, 2018-08, Vol.156, p.79-92</ispartof><rights>2018 Elsevier Masson SAS</rights><rights>Copyright © 2018 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-426bde1d01fef97071d48079b3df28ab8c053a313ccda3633d95c8ca9553b85d3</citedby><cites>FETCH-LOGICAL-c463t-426bde1d01fef97071d48079b3df28ab8c053a313ccda3633d95c8ca9553b85d3</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.2018.06.008$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30006176$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wilson, Kenneth J.</creatorcontrib><creatorcontrib>Xiao, Jingbo</creatorcontrib><creatorcontrib>Chen, Catherine Z.</creatorcontrib><creatorcontrib>Huang, Zaohua</creatorcontrib><creatorcontrib>Agoulnik, Irina U.</creatorcontrib><creatorcontrib>Ferrer, Marc</creatorcontrib><creatorcontrib>Southall, Noel</creatorcontrib><creatorcontrib>Hu, Xin</creatorcontrib><creatorcontrib>Zheng, Wei</creatorcontrib><creatorcontrib>Xu, Xin</creatorcontrib><creatorcontrib>Wang, Amy</creatorcontrib><creatorcontrib>Myhr, Courtney</creatorcontrib><creatorcontrib>Barnaeva, Elena</creatorcontrib><creatorcontrib>George, Emmett R.</creatorcontrib><creatorcontrib>Agoulnik, Alexander I.</creatorcontrib><creatorcontrib>Marugan, Juan J.</creatorcontrib><title>Optimization of the first small-molecule relaxin/insulin-like family peptide receptor (RXFP1) agonists: Activation results in an antifibrotic gene expression profile</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>A dose responsive quantitative high throughput screen (qHTS) of >350,000 compounds against a human relaxin/insulin-like family peptide receptor (RXFP1) transfected HEK293 cell line identified 2-acetamido-N-phenylbenzamides 1 and 3 with modest agonist activity. An extensive structure-activity study has been undertaken to optimize the potency, efficacy, and physical properties of the series, resulting in the identification of compound 65 (ML-290), which has excellent in vivo PK properties with high levels of systemic exposure. This series, exemplified by 65, has produced first-in-class small-molecule agonists of RXFP1 and is a potent activator of anti-fibrotic genes.
[Display omitted]
•A high throughput screening campaign identified the first small molecule relaxin peptide hormone receptor agonists.•An extensive medicinal chemistry effort produced an optimized, potent lead compound.•Pharmokinetic studies show good compound bioavailability in mice with no observed toxicity.•The lead compound displays an antifibrotic gene expression profile in activated human hepatic stellate cells.</description><subject>2-Acetamido-N-Phenylbenzamide</subject><subject>Animals</subject><subject>Antifibrotic</subject><subject>Benzamides - chemistry</subject><subject>Benzamides - pharmacokinetics</subject><subject>Benzamides - pharmacology</subject><subject>Cell Line</subject><subject>G-protein coupled receptor</subject><subject>HEK293 Cells</subject><subject>Hepatic Stellate Cells - drug effects</subject><subject>Hepatic Stellate Cells - metabolism</subject><subject>Hepatic Stellate Cells - pathology</subject><subject>Humans</subject><subject>Liver Cirrhosis - drug therapy</subject><subject>Liver Cirrhosis - genetics</subject><subject>Liver Cirrhosis - metabolism</subject><subject>Liver Cirrhosis - pathology</subject><subject>Mice, Inbred C57BL</subject><subject>Models, Molecular</subject><subject>Receptors, G-Protein-Coupled - agonists</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Receptors, Peptide - agonists</subject><subject>Receptors, Peptide - metabolism</subject><subject>Relaxin</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - pharmacokinetics</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>Transcriptome - drug effects</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kVFrFDEUhQdR7Lb6D0TyqA8zTSYzmVkfhFJsFQoVUfAtZJI7u3fNJEOSXVr_j__TDKtVX4RALuSc7yQ5RfGC0YpRJs53Fewm0NuqpqyvqKgo7R8VK9aJvuR12zwuVrSuednWvDkpTmPcUUpbQenT4oTnUWTlqvhxOyec8LtK6B3xI0lbICOGmEiclLXl5C3ovQUSwKo7dOfo4t6iKy1-y0o1ob0nM2SKWTQ6Tz6QV5--Xn1kr4naeIcxxTfkQic8HFMCZEKKBB1Ry0o44hB8Qk024IDA3ZwlcZHOwY9o4VnxZFQ2wvNf-1nx5erd58v35c3t9YfLi5tSN4KnsqnFYIAZykYY1x3tmGl62q0Hbsa6V0OvacsVZ1xro7jg3Kxb3Wu1bls-9K3hZ8XbI3feDxMYDS4FZeUccFLhXnqF8t8Th1u58QcpGK1p12RAcwTo4GMMMD54GZVLbXInj7XJpTZJhcy1ZdvLv3MfTL97-nMxyK8_IAQZNYLTYDD_eZLG4_8TfgI1FbDr</recordid><startdate>20180805</startdate><enddate>20180805</enddate><creator>Wilson, Kenneth J.</creator><creator>Xiao, Jingbo</creator><creator>Chen, Catherine Z.</creator><creator>Huang, Zaohua</creator><creator>Agoulnik, Irina U.</creator><creator>Ferrer, Marc</creator><creator>Southall, Noel</creator><creator>Hu, Xin</creator><creator>Zheng, Wei</creator><creator>Xu, Xin</creator><creator>Wang, Amy</creator><creator>Myhr, Courtney</creator><creator>Barnaeva, Elena</creator><creator>George, Emmett R.</creator><creator>Agoulnik, Alexander I.</creator><creator>Marugan, Juan J.</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>5PM</scope></search><sort><creationdate>20180805</creationdate><title>Optimization of the first small-molecule relaxin/insulin-like family peptide receptor (RXFP1) agonists: Activation results in an antifibrotic gene expression profile</title><author>Wilson, Kenneth J. ; Xiao, Jingbo ; Chen, Catherine Z. ; Huang, Zaohua ; Agoulnik, Irina U. ; Ferrer, Marc ; Southall, Noel ; Hu, Xin ; Zheng, Wei ; Xu, Xin ; Wang, Amy ; Myhr, Courtney ; Barnaeva, Elena ; George, Emmett R. ; Agoulnik, Alexander I. ; Marugan, Juan J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-426bde1d01fef97071d48079b3df28ab8c053a313ccda3633d95c8ca9553b85d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>2-Acetamido-N-Phenylbenzamide</topic><topic>Animals</topic><topic>Antifibrotic</topic><topic>Benzamides - chemistry</topic><topic>Benzamides - pharmacokinetics</topic><topic>Benzamides - pharmacology</topic><topic>Cell Line</topic><topic>G-protein coupled receptor</topic><topic>HEK293 Cells</topic><topic>Hepatic Stellate Cells - drug effects</topic><topic>Hepatic Stellate Cells - metabolism</topic><topic>Hepatic Stellate Cells - pathology</topic><topic>Humans</topic><topic>Liver Cirrhosis - drug therapy</topic><topic>Liver Cirrhosis - genetics</topic><topic>Liver Cirrhosis - metabolism</topic><topic>Liver Cirrhosis - pathology</topic><topic>Mice, Inbred C57BL</topic><topic>Models, Molecular</topic><topic>Receptors, G-Protein-Coupled - agonists</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Receptors, Peptide - agonists</topic><topic>Receptors, Peptide - metabolism</topic><topic>Relaxin</topic><topic>Small Molecule Libraries - chemistry</topic><topic>Small Molecule Libraries - pharmacokinetics</topic><topic>Small Molecule Libraries - pharmacology</topic><topic>Transcriptome - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wilson, Kenneth J.</creatorcontrib><creatorcontrib>Xiao, Jingbo</creatorcontrib><creatorcontrib>Chen, Catherine Z.</creatorcontrib><creatorcontrib>Huang, Zaohua</creatorcontrib><creatorcontrib>Agoulnik, Irina U.</creatorcontrib><creatorcontrib>Ferrer, Marc</creatorcontrib><creatorcontrib>Southall, Noel</creatorcontrib><creatorcontrib>Hu, Xin</creatorcontrib><creatorcontrib>Zheng, Wei</creatorcontrib><creatorcontrib>Xu, Xin</creatorcontrib><creatorcontrib>Wang, Amy</creatorcontrib><creatorcontrib>Myhr, Courtney</creatorcontrib><creatorcontrib>Barnaeva, Elena</creatorcontrib><creatorcontrib>George, Emmett R.</creatorcontrib><creatorcontrib>Agoulnik, Alexander I.</creatorcontrib><creatorcontrib>Marugan, Juan J.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wilson, Kenneth J.</au><au>Xiao, Jingbo</au><au>Chen, Catherine Z.</au><au>Huang, Zaohua</au><au>Agoulnik, Irina U.</au><au>Ferrer, Marc</au><au>Southall, Noel</au><au>Hu, Xin</au><au>Zheng, Wei</au><au>Xu, Xin</au><au>Wang, Amy</au><au>Myhr, Courtney</au><au>Barnaeva, Elena</au><au>George, Emmett R.</au><au>Agoulnik, Alexander I.</au><au>Marugan, Juan J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Optimization of the first small-molecule relaxin/insulin-like family peptide receptor (RXFP1) agonists: Activation results in an antifibrotic gene expression profile</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2018-08-05</date><risdate>2018</risdate><volume>156</volume><spage>79</spage><epage>92</epage><pages>79-92</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>A dose responsive quantitative high throughput screen (qHTS) of >350,000 compounds against a human relaxin/insulin-like family peptide receptor (RXFP1) transfected HEK293 cell line identified 2-acetamido-N-phenylbenzamides 1 and 3 with modest agonist activity. An extensive structure-activity study has been undertaken to optimize the potency, efficacy, and physical properties of the series, resulting in the identification of compound 65 (ML-290), which has excellent in vivo PK properties with high levels of systemic exposure. This series, exemplified by 65, has produced first-in-class small-molecule agonists of RXFP1 and is a potent activator of anti-fibrotic genes.
[Display omitted]
•A high throughput screening campaign identified the first small molecule relaxin peptide hormone receptor agonists.•An extensive medicinal chemistry effort produced an optimized, potent lead compound.•Pharmokinetic studies show good compound bioavailability in mice with no observed toxicity.•The lead compound displays an antifibrotic gene expression profile in activated human hepatic stellate cells.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>30006176</pmid><doi>10.1016/j.ejmech.2018.06.008</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0223-5234 |
| ispartof | European journal of medicinal chemistry, 2018-08, Vol.156, p.79-92 |
| issn | 0223-5234 1768-3254 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6102074 |
| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | 2-Acetamido-N-Phenylbenzamide Animals Antifibrotic Benzamides - chemistry Benzamides - pharmacokinetics Benzamides - pharmacology Cell Line G-protein coupled receptor HEK293 Cells Hepatic Stellate Cells - drug effects Hepatic Stellate Cells - metabolism Hepatic Stellate Cells - pathology Humans Liver Cirrhosis - drug therapy Liver Cirrhosis - genetics Liver Cirrhosis - metabolism Liver Cirrhosis - pathology Mice, Inbred C57BL Models, Molecular Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - metabolism Receptors, Peptide - agonists Receptors, Peptide - metabolism Relaxin Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacokinetics Small Molecule Libraries - pharmacology Transcriptome - drug effects |
| title | Optimization of the first small-molecule relaxin/insulin-like family peptide receptor (RXFP1) agonists: Activation results in an antifibrotic gene expression profile |
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