Abstract
Following on from ezutromid, the first-in-class benzoxazole utrophin modulator that progressed to Phase 2 clinical trials for the treatment of Duchenne muscular dystrophy, a new chemotype was designed to optimise its physicochemical and ADME profile. Herein we report the synthesis of SMT022357, a second generation utrophin modulator preclinical candidate, and an asymmetric synthesis of its constituent enantiomers. The pharmacological properties of both enantiomers were evaluated in vitro and in vivo. No significant difference in the activity or efficacy was observed between the two enantiomers; activity was found to be comparable to the racemic mixture.
Highlights
Duchenne muscular dystrophy (DMD) is an X linked, recessive, fatal, muscle-wasting disease [1]
Dystrophin is essential for muscle membrane stability as it acts as a linker between the internal cytoskeleton of the muscle cell and the extracellular matrix to form the dystrophinassociated protein complex (DAPC) at the sarcolemma [3]
Provide stability to muscle cells in a similar role to dystrophin but at different stages of fibre maturity. This has the advantage over the other treatments in development in that it should be successful in treating all patients, regardless of the genetic mutation responsible for their illness [9], and it does not require immunosuppression [7]
Summary
Duchenne muscular dystrophy (DMD) is an X linked, recessive, fatal, muscle-wasting disease [1]. Provide stability to muscle cells in a similar role to dystrophin but at different stages of fibre maturity This has the advantage over the other treatments in development in that it should be successful in treating all patients, regardless of the genetic mutation responsible for their illness [9], and it does not require immunosuppression [7]. In this context, ezutromid (Fig. 1), developed by Summit Therapeutics plc, has been the first orally bioavailable small molecule designed to target the utrophin-A promoter. We report the synthesis of SMT022357, its resolution into, and de novo enantioselective synthesis of, its constituent enantiomers and the preliminary results of their in vivo efficacy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
