Isolation, structural identification, synthesis, and pharmacological profiling of 1,2-trans-dihydro-1,2-diol metabolites of the utrophin modulator ezutromid.
Chatzopoulou M., Claridge TDW., Davies KE., Davies SG., Elsey D., Emer E., Fletcher AM., Harriman S., Robinson N., Rowley J., Russell AJ., Tinsley J., Weaver R., Wilkinson I., Willis N., Wilson F., Wynne GM.
5-(Ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole (ezutromid, 1) is a first in class utrophin modulator which 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 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 in vitro systems. We further elucidate the likely metabolic pathway and CYP450 isoforms responsible for DHD1 and DHD3 production and characterise their physicochemical, ADME, pharmacological properties and preliminary toxicological profile.