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

Abstract

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 pIC50 in HepG2 cells, hence leading to a potentially safer toxicological profiles in this series. Compound 21 showed a balanced profile (H2K EC50: 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.

Critical Assessment of pH‐Dependent Lipophilicity Profiles of Small Molecules: Which One Should We Use and In Which Cases?

“…Lipophilicity has been a relevant physicochemical property in pharmaceutical research since the late 1800s, where the toxicity and anesthetic properties of several substances have been correlated to their solubilities in water and oil/water partition coefficients [1] . In addition, this property has also been associated with several pharmacokinetic properties, such as enzyme binding, [2] toxicity, [3] solubility, [4] membrane permeability, [5] and bioaccumulation [6] . Thus, lipophilicity has been considered a significant descriptor in drug discovery metrics, such as Lipinski's [7] and Veber's [8] empirical rules, which are intended to optimize oral bioavailability for drug‐like compounds.…”

Multimetallic Pd- and Ni-catalyzed C(sp2)–P cross-coupling under aqueous micellar conditions

“…Isosterically replacing phosphates by more metabolically stable phosphonates has fostered the development of life-saving antiviral 11 and antibacterial 12 drugs and prodrugs 13 because they retain the bioactivity of the original phosphates. 10,14 Several bioactive phosphonates, phosphinates and phosphine oxides have also been applied in drug discovery and development, 2 a ,3,7,15–18 yielding fosdevirine, a non-nucleoside reverse transcriptase inhibitor (Fig. 1A), 19 and efonidipine, a calcium channel blocker, 20 in addition to eukaryotic initiation factor 4E (eIF4E) inhibitors.…”

Enantioselective Synthesis of Versatile Stereogenic-at-P(V) Building Blocks via Hydrogen-Bond-Donor Catalysis

“…4B) (22). This three-step route to phosphinate esters was applied to the synthesis of (+)-SMT022332, a utrophin modulator developed as a potential treatment for Duchenne Muscular Dystrophy (36)(37)(38). An analogue of (+)-SMT022332 was previously accessed in 83% ee and 5% overall yield using a chiral auxiliary-based approach (4).…”