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
  • 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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