2-Arylbenzo[d]oxazole Phosphinate Esters as Second-Generation Modulators of Utrophin for the Treatment of Duchenne Muscular Dystrophy
- 18 June 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (14), 7880-7891
- https://doi.org/10.1021/acs.jmedchem.0c00807
Abstract
Utrophin modulation is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD), which should be applicable to all patient populations. Following on from ezutromid, the first-generation utrophin modulator, we describe the development of a second generation of utrophin modulators, based on the bioisosteric replacement of the sulfone group with a phosphinate ester and substitution of the metabolically labile naphthalene with a haloaryl substituent. The improved physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties, further reflected in the enhanced pharmacokinetic profile of the most advanced compounds, 30 and 27, led to significantly better in vivo exposure compared to ezutromid and alleviation of the dystrophic phenotype in mdx mice. While 30 was found to have dose-limiting hepatotoxicity, 27 and its enantiomers exhibited limited off-target effects, resulting in a safe profile and highlighting their potential utility as next-generation utrophin modulators suitable for progression toward a future DMD therapy.Keywords
Funding Information
- Medical Research Council (1501AV003/CA2)
- Duchenne UK
- Summit Therapeutics plc
This publication has 21 references indexed in Scilit:
- Mutation-Based Therapeutic Strategies for Duchenne Muscular Dystrophy: From Genetic Diagnosis to TherapyJournal of Personalized Medicine, 2019
- The potential of utrophin modulators for the treatment of Duchenne muscular dystrophyExpert Opinion on Orphan Drugs, 2018
- Pharmacological advances for treatment in Duchenne muscular dystrophyCurrent Opinion in Pharmacology, 2017
- The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence reviewOrphanet Journal of Rare Diseases, 2017
- Safety, Tolerability, and Pharmacokinetics of SMT C1100, a 2-Arylbenzoxazole Utrophin Modulator, following Single- and Multiple-Dose Administration to Pediatric Patients with Duchenne Muscular DystrophyPLOS ONE, 2016
- Second-generation compound for the modulation of utrophin in the therapy of DMDHuman Molecular Genetics, 2015
- Safety, tolerability, and pharmacokinetics of SMT C1100, a 2‐arylbenzoxazole utrophin modulator, following single‐ and multiple‐dose administration to healthy male adult volunteersThe Journal of Clinical Pharmacology, 2015
- Expression of full-length utrophin prevents muscular dystrophy in mdx miceNature Medicine, 1998
- Expression of truncated utrophin leads to major functional improvements in dystrophin-deficient muscles of miceNature Medicine, 1997
- An autosomal transcript in skeletal muscle with homology to dystrophinNature, 1989