Compound class:
Synthetic organic
Comment: Compound 27 was designed to offer improved clinical potential as a utrophin modulator than either ezutromid (failed at Phase 2) or SMT022357 (terminated at preclinical) [1]. This entry shows the compound without specified stereochemistry, to represent the racemic mixture. (+)-27 is slightly more active than (-)-27 or the racemate in vitro.
Clinical rationale: Up-regulation of utrophin (UTRN; P46939) as being investigated as a disease-modifying approach for Duchenne muscular dystrophy (DMD). In the mdx mouse DMD model, increased levels of utrophin effectively acts as a substitute for the dystrophin (DMD; P11532) that is missing in DMD [2]. |
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Bioactivity Comments |
Compound 27 achieves significantly improved in vivo exposure compared to ezutromid and it reduces the dystrophic phenotype in mdx mice [1]. Compound 27 activates the utrophin promoter in a cellular H2K-mdx reporter gene assay (EC50 244 nM) and increases utrophin protein levels up to 2.5-fold (by western blot) in LUmdx cells. |