Decreasing HepG2 Cytotoxicity by Lowering the Lipophilicity of Benzo[d]oxazolephosphinate Ester Utrophin Modulators.

Utrophin modulation is a disease-modifying therapeutic strategy for Duchenne muscular dystrophy that would be applicable to all patient populations. To improve the suboptimal profile of ezutromid, the first-in-class clinical candidate, a second generation of utrophin modulators bearing a phosphinate ester moiety was developed. This modification significantly improved the physicochemical and ADME properties, but one of the main lead molecules was found to have dose-limiting hepatotoxicity. In this work we describe how less lipophilic analogues retained utrophin modulatory activity in a reporter gene assay, upregulated utrophin protein in dystrophic mouse muscle cells, but also had improved physicochemical and ADME properties. Notably, ClogP was found to directly correlate with pIC ₅₀ in HepG2 cells, hence leading to a potentially safer toxicological profiles in this series. Compound 21 showed a balanced profile (H2K EC ₅₀ : 4.17 μM, solubility: 477 μM, mouse hepatocyte T _1/2 > 240 min) and increased utrophin protein 1.6-fold in a Western blot assay.
Competing Interests: The authors declare the following competing financial interest(s): S.H. and F.X.W. are or were Summit Therapeutics plc employees or consultants at the time that the work was conducted. K.E.D., S.G.D. and A.J.R. are minor shareholders of Summit Therapeutics plc.
(© 2020 American Chemical Society.)