2. Academic Validation
  3. Structure-activity relationships of 2-pyrimidinecarbohydrazides as utrophin modulators for the potential treatment of Duchenne muscular dystrophy

Structure-activity relationships of 2-pyrimidinecarbohydrazides as utrophin modulators for the potential treatment of Duchenne muscular dystrophy

  • Bioorg Med Chem. 2022 Sep 1;69:116812. doi: 10.1016/j.bmc.2022.116812.
Maria Chatzopoulou 1,  Daniel Conole 1,  Enrico Emer 1,  Jessica A Rowley 1,  Nicky J Willis 1,  Sarah E Squire 2,  Becky Gill 3,  Steve Brough 3,  Francis X Wilson 4,  Graham M Wynne 1,  Stephen G Davies 1,  Kay E Davies 2,  Angela J Russell 5
Affiliations

Affiliations

  • 1 Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
  • 2 Department of Physiology, Anatomy and Genetics, University of Oxford, Sir Henry Wellcome Building of Gene Function, South Parks Road, Oxford OX1 3PT, UK.
  • 3 Key Organics Ltd, Highfield Road Industrial Estate, Camelford, Cornwall PL32 9RA, UK.
  • 4 Summit Therapeutics Plc, 136a Eastern Avenue, Milton Park, Abingdon, Oxfordshire OX14 4SB, UK.
  • 5 Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK; Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3PQ, UK.
PMID: 35772287 DOI: 10.1016/j.bmc.2022.116812
Abstract

A therapeutic approach that holds the potential to treat all Duchenne muscular dystrophy (DMD) patient populations is utrophin modulation. Ezutromid, a first generation utrophin modulator which was later found to act via antagonism of the arylhydrocarbon receptor, progressed to Phase 2 clinical trials. Although interim data showed target engagement and functional improvements, ezutromid ultimately failed to meet its clinical endpoints. We recently described the identification of a new class of hydrazide utrophin modulators which has a different mechanism of action to ezutromid. In this study we report our early optimisation studies on this hydrazide series. The new analogues had significantly improved potency in cell-based assays, increased sp3 character and reduced lipophilicity, which also improved their physicochemical properties. A representative new analogue combining these attributes increased utrophin protein in dystrophic mouse cells showing it can be used as a chemical tool to reveal new insights regarding utrophin upregulation as a strategy for DMD therapeutic intervention.

Keywords

Carbohydrazide; Duchenne muscular dystrophy; LUmdx; Phenotypic screening; Utrophin modulator.

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