Structure-activity relationships of 2-pyrimidinecarbohydrazides as utrophin modulators for the potential treatment of Duchenne muscular dystrophy
[Display omitted] A therapeutic approach that holds the potential to treat all Duchenne muscular dystrophy (DMD) patient populations is utrophin modulation. Ezutromid, a first generation utrophin modulator which was later found to act via antagonism of the arylhydrocarbon receptor, progressed to Pha...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2022-09, Vol.69, p.116812-116812, Article 116812 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Chatzopoulou, Maria Conole, Daniel Emer, Enrico Rowley, Jessica A. Willis, Nicky J. Squire, Sarah E. Gill, Becky Brough, Steve Wilson, Francis X. Wynne, Graham M. Davies, Stephen G. Davies, Kay E. Russell, Angela J. |
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A therapeutic approach that holds the potential to treat all Duchenne muscular dystrophy (DMD) patient populations is utrophin modulation. Ezutromid, a first generation utrophin modulator which was later found to act via antagonism of the arylhydrocarbon receptor, progressed to Phase 2 clinical trials. Although interim data showed target engagement and functional improvements, ezutromid ultimately failed to meet its clinical endpoints. We recently described the identification of a new class of hydrazide utrophin modulators which has a different mechanism of action to ezutromid. In this study we report our early optimisation studies on this hydrazide series. The new analogues had significantly improved potency in cell-based assays, increased sp3 character and reduced lipophilicity, which also improved their physicochemical properties. A representative new analogue combining these attributes increased utrophin protein in dystrophic mouse cells showing it can be used as a chemical tool to reveal new insights regarding utrophin upregulation as a strategy for DMD therapeutic intervention. |
| doi_str_mv | 10.1016/j.bmc.2022.116812 |
| format | Article |
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A therapeutic approach that holds the potential to treat all Duchenne muscular dystrophy (DMD) patient populations is utrophin modulation. Ezutromid, a first generation utrophin modulator which was later found to act via antagonism of the arylhydrocarbon receptor, progressed to Phase 2 clinical trials. Although interim data showed target engagement and functional improvements, ezutromid ultimately failed to meet its clinical endpoints. We recently described the identification of a new class of hydrazide utrophin modulators which has a different mechanism of action to ezutromid. In this study we report our early optimisation studies on this hydrazide series. The new analogues had significantly improved potency in cell-based assays, increased sp3 character and reduced lipophilicity, which also improved their physicochemical properties. A representative new analogue combining these attributes increased utrophin protein in dystrophic mouse cells showing it can be used as a chemical tool to reveal new insights regarding utrophin upregulation as a strategy for DMD therapeutic intervention.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2022.116812</identifier><identifier>PMID: 35772287</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Carbohydrazide ; Duchenne muscular dystrophy ; Hydrazines - pharmacology ; Hydrazines - therapeutic use ; LUmdx ; Mice ; Muscle, Skeletal - metabolism ; Muscular Dystrophy, Duchenne - drug therapy ; Muscular Dystrophy, Duchenne - metabolism ; Phenotypic screening ; Structure-Activity Relationship ; Up-Regulation ; Utrophin - genetics ; Utrophin - metabolism ; Utrophin - therapeutic use ; Utrophin modulator</subject><ispartof>Bioorganic & medicinal chemistry, 2022-09, Vol.69, p.116812-116812, Article 116812</ispartof><rights>2022 The Authors</rights><rights>Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c396t-278d16a954c0a2b62d1e7a1aaf21077b6a2d35860e759b1d1f70c7068267eca83</citedby><cites>FETCH-LOGICAL-c396t-278d16a954c0a2b62d1e7a1aaf21077b6a2d35860e759b1d1f70c7068267eca83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089622002048$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35772287$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chatzopoulou, Maria</creatorcontrib><creatorcontrib>Conole, Daniel</creatorcontrib><creatorcontrib>Emer, Enrico</creatorcontrib><creatorcontrib>Rowley, Jessica A.</creatorcontrib><creatorcontrib>Willis, Nicky J.</creatorcontrib><creatorcontrib>Squire, Sarah E.</creatorcontrib><creatorcontrib>Gill, Becky</creatorcontrib><creatorcontrib>Brough, Steve</creatorcontrib><creatorcontrib>Wilson, Francis X.</creatorcontrib><creatorcontrib>Wynne, Graham M.</creatorcontrib><creatorcontrib>Davies, Stephen G.</creatorcontrib><creatorcontrib>Davies, Kay E.</creatorcontrib><creatorcontrib>Russell, Angela J.</creatorcontrib><title>Structure-activity relationships of 2-pyrimidinecarbohydrazides as utrophin modulators for the potential treatment of Duchenne muscular dystrophy</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
A therapeutic approach that holds the potential to treat all Duchenne muscular dystrophy (DMD) patient populations is utrophin modulation. Ezutromid, a first generation utrophin modulator which was later found to act via antagonism of the arylhydrocarbon receptor, progressed to Phase 2 clinical trials. Although interim data showed target engagement and functional improvements, ezutromid ultimately failed to meet its clinical endpoints. We recently described the identification of a new class of hydrazide utrophin modulators which has a different mechanism of action to ezutromid. In this study we report our early optimisation studies on this hydrazide series. The new analogues had significantly improved potency in cell-based assays, increased sp3 character and reduced lipophilicity, which also improved their physicochemical properties. A representative new analogue combining these attributes increased utrophin protein in dystrophic mouse cells showing it can be used as a chemical tool to reveal new insights regarding utrophin upregulation as a strategy for DMD therapeutic intervention.</description><subject>Animals</subject><subject>Carbohydrazide</subject><subject>Duchenne muscular dystrophy</subject><subject>Hydrazines - pharmacology</subject><subject>Hydrazines - therapeutic use</subject><subject>LUmdx</subject><subject>Mice</subject><subject>Muscle, Skeletal - metabolism</subject><subject>Muscular Dystrophy, Duchenne - drug therapy</subject><subject>Muscular Dystrophy, Duchenne - metabolism</subject><subject>Phenotypic screening</subject><subject>Structure-Activity Relationship</subject><subject>Up-Regulation</subject><subject>Utrophin - genetics</subject><subject>Utrophin - metabolism</subject><subject>Utrophin - therapeutic use</subject><subject>Utrophin modulator</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtv1DAUhS1ERYfCD2CDvGSTwXYyfogVanlJlVi0XVuOfaN4lMTBj0rhX_CP8TCFJaurK53zSecchN5QsqeE8vfHfT_bPSOM7SnlkrJnaEc73jVtq-hztCOKy4ZIxS_Ry5SOhBDWKfoCXbYHIRiTYod-3eVYbC4RGmOzf_R5wxEmk31Y0ujXhMOAWbNu0c_e-QWsiX0YNxfNT-8gYZNwyTGso1_wHFyp1hATHkLEeQS8hgxL9mbCOYLJc31OxJtiR1gWwHNJtnoidlv6g9leoYvBTAleP90r9PD50_311-b2-5dv1x9vG9sqnhsmpKPcqENniWE9Z46CMNSYgVEiRM8Nc-1BcgLioHrq6CCIFYRLxkUNIdsr9O7MXWP4USBlPftkYZrMAqEkzbjsiFKtYlVKz1IbQ0oRBr3WOkzcNCX6tIQ-6rqEPi2hz0tUz9snfOlncP8cf6uvgg9nAdSQjx6iTtbDYsH5CDZrF_x_8L8BTgKdeQ</recordid><startdate>20220901</startdate><enddate>20220901</enddate><creator>Chatzopoulou, Maria</creator><creator>Conole, Daniel</creator><creator>Emer, Enrico</creator><creator>Rowley, Jessica A.</creator><creator>Willis, Nicky J.</creator><creator>Squire, Sarah E.</creator><creator>Gill, Becky</creator><creator>Brough, Steve</creator><creator>Wilson, Francis X.</creator><creator>Wynne, Graham M.</creator><creator>Davies, Stephen G.</creator><creator>Davies, Kay E.</creator><creator>Russell, Angela J.</creator><general>Elsevier Ltd</general><scope>6I.</scope><scope>AAFTH</scope><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>20220901</creationdate><title>Structure-activity relationships of 2-pyrimidinecarbohydrazides as utrophin modulators for the potential treatment of Duchenne muscular dystrophy</title><author>Chatzopoulou, Maria ; Conole, Daniel ; Emer, Enrico ; Rowley, Jessica A. ; Willis, Nicky J. ; Squire, Sarah E. ; Gill, Becky ; Brough, Steve ; Wilson, Francis X. ; Wynne, Graham M. ; Davies, Stephen G. ; Davies, Kay E. ; Russell, Angela J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c396t-278d16a954c0a2b62d1e7a1aaf21077b6a2d35860e759b1d1f70c7068267eca83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Carbohydrazide</topic><topic>Duchenne muscular dystrophy</topic><topic>Hydrazines - pharmacology</topic><topic>Hydrazines - therapeutic use</topic><topic>LUmdx</topic><topic>Mice</topic><topic>Muscle, Skeletal - metabolism</topic><topic>Muscular Dystrophy, Duchenne - drug therapy</topic><topic>Muscular Dystrophy, Duchenne - metabolism</topic><topic>Phenotypic screening</topic><topic>Structure-Activity Relationship</topic><topic>Up-Regulation</topic><topic>Utrophin - genetics</topic><topic>Utrophin - metabolism</topic><topic>Utrophin - therapeutic use</topic><topic>Utrophin modulator</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chatzopoulou, Maria</creatorcontrib><creatorcontrib>Conole, Daniel</creatorcontrib><creatorcontrib>Emer, Enrico</creatorcontrib><creatorcontrib>Rowley, Jessica A.</creatorcontrib><creatorcontrib>Willis, Nicky J.</creatorcontrib><creatorcontrib>Squire, Sarah E.</creatorcontrib><creatorcontrib>Gill, Becky</creatorcontrib><creatorcontrib>Brough, Steve</creatorcontrib><creatorcontrib>Wilson, Francis X.</creatorcontrib><creatorcontrib>Wynne, Graham M.</creatorcontrib><creatorcontrib>Davies, Stephen G.</creatorcontrib><creatorcontrib>Davies, Kay E.</creatorcontrib><creatorcontrib>Russell, Angela J.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><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>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chatzopoulou, Maria</au><au>Conole, Daniel</au><au>Emer, Enrico</au><au>Rowley, Jessica A.</au><au>Willis, Nicky J.</au><au>Squire, Sarah E.</au><au>Gill, Becky</au><au>Brough, Steve</au><au>Wilson, Francis X.</au><au>Wynne, Graham M.</au><au>Davies, Stephen G.</au><au>Davies, Kay E.</au><au>Russell, Angela J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-activity relationships of 2-pyrimidinecarbohydrazides as utrophin modulators for the potential treatment of Duchenne muscular dystrophy</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2022-09-01</date><risdate>2022</risdate><volume>69</volume><spage>116812</spage><epage>116812</epage><pages>116812-116812</pages><artnum>116812</artnum><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
A therapeutic approach that holds the potential to treat all Duchenne muscular dystrophy (DMD) patient populations is utrophin modulation. Ezutromid, a first generation utrophin modulator which was later found to act via antagonism of the arylhydrocarbon receptor, progressed to Phase 2 clinical trials. Although interim data showed target engagement and functional improvements, ezutromid ultimately failed to meet its clinical endpoints. We recently described the identification of a new class of hydrazide utrophin modulators which has a different mechanism of action to ezutromid. In this study we report our early optimisation studies on this hydrazide series. The new analogues had significantly improved potency in cell-based assays, increased sp3 character and reduced lipophilicity, which also improved their physicochemical properties. A representative new analogue combining these attributes increased utrophin protein in dystrophic mouse cells showing it can be used as a chemical tool to reveal new insights regarding utrophin upregulation as a strategy for DMD therapeutic intervention.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>35772287</pmid><doi>10.1016/j.bmc.2022.116812</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Carbohydrazide Duchenne muscular dystrophy Hydrazines - pharmacology Hydrazines - therapeutic use LUmdx Mice Muscle, Skeletal - metabolism Muscular Dystrophy, Duchenne - drug therapy Muscular Dystrophy, Duchenne - metabolism Phenotypic screening Structure-Activity Relationship Up-Regulation Utrophin - genetics Utrophin - metabolism Utrophin - therapeutic use Utrophin modulator |
| title | Structure-activity relationships of 2-pyrimidinecarbohydrazides as utrophin modulators for the potential treatment of Duchenne muscular dystrophy |
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