2. Academic Validation
  3. Isolation, Structural Identification, Synthesis, and Pharmacological Profiling of 1,2- trans-Dihydro-1,2-diol Metabolites of the Utrophin Modulator Ezutromid

Isolation, Structural Identification, Synthesis, and Pharmacological Profiling of 1,2- trans-Dihydro-1,2-diol Metabolites of the Utrophin Modulator Ezutromid

  • J Med Chem. 2020 Mar 12;63(5):2547-2556. doi: 10.1021/acs.jmedchem.9b01547.
Maria Chatzopoulou 1,  Tim D W Claridge 1,  Kay E Davies 2,  Stephen G Davies 1,  David J Elsey 3,  Enrico Emer 1,  Ai M Fletcher 1,  Shawn Harriman 4,  Neil Robinson 5,  Jessica A Rowley 1,  Angela J Russell 1 6,  Jonathon M Tinsley 3,  Richard Weaver 7,  Isabel V L Wilkinson 1,  Nicky J Willis 1,  Francis X Wilson 3,  Graham M Wynne 1
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, United Kingdom.
  • 2 Department of Physiology, Anatomy and Genetics, MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford OX1 3PT, United Kingdom.
  • 3 Summit Therapeutics plc, 136a Eastern Avenue, Milton Park, Abingdon OX14 4SB, United Kingdom.
  • 4 Summit Therapeutics plc, One Broadway, 14th Floor, Cambridge, Massachusetts 02142, United States.
  • 5 S.H.B. Enterprises Ltd., 55 Station Road, Beaconsfield HP19 1QL, United Kingdom.
  • 6 Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3PQ, United Kingdom.
  • 7 XenoGesis Ltd., BioCity Nottingham, Pennyfoot Street, Nottingham NG1 1GF, United Kingdom.
PMID: 31599580 DOI: 10.1021/acs.jmedchem.9b01547
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.

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