Isolation, structural identification, synthesis, and pharmacological profiling of 1,2-trans-dihydro-1,2-diol metabolites of the utrophin modulator ezutromid
5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (ezutromid, 1) is a first-in-class utrophin modulator that has been evaluated in a phase 2 clinical study for the treatment of Duchenne muscular dystrophy (DMD). Ezutromid was found to undergo hepatic oxidation of its 2-naphthyl substituent to pro...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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American Chemical Society
2019
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| _version_ | 1826258717946937344 |
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| author | Chatzopoulou, M Claridge, T Davies, K Davies, S Elsey, D Emer, E Fletcher, A Harriman, S Robinson, N Rowley, J Russell, A Tinsley, J Weaver, R Wilkinson, I Willis, N Wilson, F Wynne, G |
| author_facet | Chatzopoulou, M Claridge, T Davies, K Davies, S Elsey, D Emer, E Fletcher, A Harriman, S Robinson, N Rowley, J Russell, A Tinsley, J Weaver, R Wilkinson, I Willis, N Wilson, F Wynne, G |
| author_sort | Chatzopoulou, M |
| collection | OXFORD |
| description | 5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (ezutromid, 1) is a first-in-class utrophin modulator that has been evaluated in a phase 2 clinical study for the treatment of Duchenne muscular dystrophy (DMD). Ezutromid was found to undergo hepatic oxidation of its 2-naphthyl substituent to produce two regioisomeric 1,2-dihydronaphthalene-1,2-diols, DHD1 and DHD3, as the major metabolites after oral administration in humans and rodents. In many patients, plasma levels of the DHD metabolites were found to exceed those of ezutromid. Herein, we describe the structural elucidation of the main metabolites of ezutromid, the regio- and relative stereochemical assignments of DHD1 and DHD3, their de novo chemical synthesis, and their production in systems in vitro. We further elucidate the likely metabolic pathway and CYP isoforms responsible for DHD1 and DHD3 production and characterize their physicochemical, ADME, and pharmacological properties and their preliminary toxicological profiles. |
| first_indexed | 2024-03-06T18:38:24Z |
| format | Journal article |
| id | oxford-uuid:0c130b25-6efe-4eac-8cc7-497f6bfbd019 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:38:24Z |
| publishDate | 2019 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:0c130b25-6efe-4eac-8cc7-497f6bfbd0192022-03-26T09:32:54ZIsolation, structural identification, synthesis, and pharmacological profiling of 1,2-trans-dihydro-1,2-diol metabolites of the utrophin modulator ezutromidJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0c130b25-6efe-4eac-8cc7-497f6bfbd019EnglishSymplectic Elements at OxfordAmerican Chemical Society2019Chatzopoulou, MClaridge, TDavies, KDavies, SElsey, DEmer, EFletcher, AHarriman, SRobinson, NRowley, JRussell, ATinsley, JWeaver, RWilkinson, IWillis, NWilson, FWynne, G5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (ezutromid, 1) is a first-in-class utrophin modulator that has been evaluated in a phase 2 clinical study for the treatment of Duchenne muscular dystrophy (DMD). Ezutromid was found to undergo hepatic oxidation of its 2-naphthyl substituent to produce two regioisomeric 1,2-dihydronaphthalene-1,2-diols, DHD1 and DHD3, as the major metabolites after oral administration in humans and rodents. In many patients, plasma levels of the DHD metabolites were found to exceed those of ezutromid. Herein, we describe the structural elucidation of the main metabolites of ezutromid, the regio- and relative stereochemical assignments of DHD1 and DHD3, their de novo chemical synthesis, and their production in systems in vitro. We further elucidate the likely metabolic pathway and CYP isoforms responsible for DHD1 and DHD3 production and characterize their physicochemical, ADME, and pharmacological properties and their preliminary toxicological profiles. |
| spellingShingle | Chatzopoulou, M Claridge, T Davies, K Davies, S Elsey, D Emer, E Fletcher, A Harriman, S Robinson, N Rowley, J Russell, A Tinsley, J Weaver, R Wilkinson, I Willis, N Wilson, F Wynne, G Isolation, structural identification, synthesis, and pharmacological profiling of 1,2-trans-dihydro-1,2-diol metabolites of the utrophin modulator ezutromid |
| title | Isolation, structural identification, synthesis, and pharmacological profiling of 1,2-trans-dihydro-1,2-diol metabolites of the utrophin modulator ezutromid |
| title_full | Isolation, structural identification, synthesis, and pharmacological profiling of 1,2-trans-dihydro-1,2-diol metabolites of the utrophin modulator ezutromid |
| title_fullStr | Isolation, structural identification, synthesis, and pharmacological profiling of 1,2-trans-dihydro-1,2-diol metabolites of the utrophin modulator ezutromid |
| title_full_unstemmed | Isolation, structural identification, synthesis, and pharmacological profiling of 1,2-trans-dihydro-1,2-diol metabolites of the utrophin modulator ezutromid |
| title_short | Isolation, structural identification, synthesis, and pharmacological profiling of 1,2-trans-dihydro-1,2-diol metabolites of the utrophin modulator ezutromid |
| title_sort | isolation structural identification synthesis and pharmacological profiling of 1 2 trans dihydro 1 2 diol metabolites of the utrophin modulator ezutromid |
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