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Synthesis of SMT022357 enantiomers and in vivo evaluation in a Duchenne muscular dystrophy mouse model
Following on from ezutromid, the first-in-class benzoxazole utrophin modulator that progressed to Phase 2 clinical trials for the treatment of Duchenne muscular dystrophy, a new chemotype was designed to optimise its physicochemical and ADME profile. Herein we report the synthesis of SMT022357, a se...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
Pergamon Press
2020
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| Materias: | |
| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369641/ https://www.ncbi.nlm.nih.gov/pubmed/32713969 http://dx.doi.org/10.1016/j.tet.2019.130819 |
| _version_ | 1783560815880699904 |
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| author | Babbs, Arran Berg, Adam Chatzopoulou, Maria Davies, Kay E. Davies, Stephen G. Edwards, Benjamin Elsey, David J. Emer, Enrico Figuccia, Aude L.A. Fletcher, Ai M. Guiraud, Simon Harriman, Shawn Moir, Lee Robinson, Neil Rowley, Jessica A. Russell, Angela J. Squire, Sarah E. Thomson, James E. Tinsley, Jonathon M. Wilson, Francis X. Wynne, Graham M. |
| author_facet | Babbs, Arran Berg, Adam Chatzopoulou, Maria Davies, Kay E. Davies, Stephen G. Edwards, Benjamin Elsey, David J. Emer, Enrico Figuccia, Aude L.A. Fletcher, Ai M. Guiraud, Simon Harriman, Shawn Moir, Lee Robinson, Neil Rowley, Jessica A. Russell, Angela J. Squire, Sarah E. Thomson, James E. Tinsley, Jonathon M. Wilson, Francis X. Wynne, Graham M. |
| author_sort | Babbs, Arran |
| collection | PubMed |
| description | Following on from ezutromid, the first-in-class benzoxazole utrophin modulator that progressed to Phase 2 clinical trials for the treatment of Duchenne muscular dystrophy, a new chemotype was designed to optimise its physicochemical and ADME profile. Herein we report the synthesis of SMT022357, a second generation utrophin modulator preclinical candidate, and an asymmetric synthesis of its constituent enantiomers. The pharmacological properties of both enantiomers were evaluated in vitro and in vivo. No significant difference in the activity or efficacy was observed between the two enantiomers; activity was found to be comparable to the racemic mixture. |
| format | Online Article Text |
| id | pubmed-7369641 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2020 |
| publisher | Pergamon Press |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-73696412020-07-23 Synthesis of SMT022357 enantiomers and in vivo evaluation in a Duchenne muscular dystrophy mouse model Babbs, Arran Berg, Adam Chatzopoulou, Maria Davies, Kay E. Davies, Stephen G. Edwards, Benjamin Elsey, David J. Emer, Enrico Figuccia, Aude L.A. Fletcher, Ai M. Guiraud, Simon Harriman, Shawn Moir, Lee Robinson, Neil Rowley, Jessica A. Russell, Angela J. Squire, Sarah E. Thomson, James E. Tinsley, Jonathon M. Wilson, Francis X. Wynne, Graham M. Tetrahedron Article Following on from ezutromid, the first-in-class benzoxazole utrophin modulator that progressed to Phase 2 clinical trials for the treatment of Duchenne muscular dystrophy, a new chemotype was designed to optimise its physicochemical and ADME profile. Herein we report the synthesis of SMT022357, a second generation utrophin modulator preclinical candidate, and an asymmetric synthesis of its constituent enantiomers. The pharmacological properties of both enantiomers were evaluated in vitro and in vivo. No significant difference in the activity or efficacy was observed between the two enantiomers; activity was found to be comparable to the racemic mixture. Pergamon Press 2020-01-10 /pmc/articles/PMC7369641/ /pubmed/32713969 http://dx.doi.org/10.1016/j.tet.2019.130819 Text en © 2019 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| spellingShingle | Article Babbs, Arran Berg, Adam Chatzopoulou, Maria Davies, Kay E. Davies, Stephen G. Edwards, Benjamin Elsey, David J. Emer, Enrico Figuccia, Aude L.A. Fletcher, Ai M. Guiraud, Simon Harriman, Shawn Moir, Lee Robinson, Neil Rowley, Jessica A. Russell, Angela J. Squire, Sarah E. Thomson, James E. Tinsley, Jonathon M. Wilson, Francis X. Wynne, Graham M. Synthesis of SMT022357 enantiomers and in vivo evaluation in a Duchenne muscular dystrophy mouse model |
| title | Synthesis of SMT022357 enantiomers and in vivo evaluation in a Duchenne muscular dystrophy mouse model |
| title_full | Synthesis of SMT022357 enantiomers and in vivo evaluation in a Duchenne muscular dystrophy mouse model |
| title_fullStr | Synthesis of SMT022357 enantiomers and in vivo evaluation in a Duchenne muscular dystrophy mouse model |
| title_full_unstemmed | Synthesis of SMT022357 enantiomers and in vivo evaluation in a Duchenne muscular dystrophy mouse model |
| title_short | Synthesis of SMT022357 enantiomers and in vivo evaluation in a Duchenne muscular dystrophy mouse model |
| title_sort | synthesis of smt022357 enantiomers and in vivo evaluation in a duchenne muscular dystrophy mouse model |
| topic | Article |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369641/ https://www.ncbi.nlm.nih.gov/pubmed/32713969 http://dx.doi.org/10.1016/j.tet.2019.130819 |
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