Abstract:
: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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Chatzopoulou M,Claridge TDW,Davies KE,Davies SG,Elsey DJ,Emer E,Fletcher AM,Harriman S,Robinson N,Rowley JA,Russell AJ,Tinsley JM,Weaver R,Wilkinson IVL,Willis NJ,Wilson FX,Wynne GMdoi
10.1021/acs.jmedchem.9b01547subject
Has Abstractpub_date
2020-03-12 00:00:00pages
2547-2556issue
5eissn
0022-2623issn
1520-4804journal_volume
63pub_type
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