1. Structure-activity relationships of 2-pyrimidinecarbohydrazides as utrophin modulators for the potential treatment of Duchenne muscular dystrophy
- Author
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Maria Chatzopoulou, Daniel Conole, Enrico Emer, Jessica A. Rowley, Nicky J. Willis, Sarah E. Squire, Becky Gill, Steve Brough, Francis X. Wilson, Graham M. Wynne, Stephen G. Davies, Kay E. Davies, and Angela J. Russell
- Subjects
Utrophin ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Up-Regulation ,Muscular Dystrophy, Duchenne ,Mice ,Structure-Activity Relationship ,Hydrazines ,Drug Discovery ,Molecular Medicine ,Animals ,Muscle, Skeletal ,Molecular Biology - 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 sp
- Published
- 2022