Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration

Abstract

Current therapeutic options for treating demyelinating disorders such as multiple sclerosis (MS) do not stimulate myelin repair, thus creating a clinical need for therapeutic agents that address axonal remyelination. Thyroid hormone is known to play an important role in promoting developmental myelination and repair, and CNS permeable thyromimetic agents could offer an increased therapeutic index compared to endogenous thyroid hormone. Sobetirome is a clinical stage thyromimetic that has been shown to have promising activity in preclinical models related to MS and X-linked adrenoleukodystrophy (X-ALD), a genetic disease that involves demyelination. Here we report a new series of sobetirome prodrugs containing ethanolamine-based promoieties that were found to undergo an intramolecular O,N acyl migration to form the pharmacologically relevant amide species. Several of these systemically administered prodrugs deliver more sobetirome to the brain compared to unmodified sobetirome. Pharmacokinetic properties of the parent drug sobetirome and amidoalcohol prodrug 3 are described and prodrug 3 was found to be more potent than sobetirome in target engagement in the brain from systemic dosing.

Myelin repair stimulated by CNS-selective thyroid hormone action

“…In addition to this first-pass metabolic processing, the oral bioavailability of Sob-AM2 is about 5-fold lower than that of sobetirome. The combination of these two issues results in a modest (~2-to 4-fold) increase in CNS sobetirome exposure provided by orally dosed Sob-AM2 compared with the same oral dose of sobetirome (20,42). This is consistent with the modest improvement in rotarod performance we observed in iCKO-Myrf mice treated with 84 μg/kg/d (p.o.)…”

“…A CNS-penetrating prodrug derivative of sobetirome, Sob-AM2, improves motor and myelin recovery in iCKO-Myrf mice. To improve the CNS penetration of sobetirome, a prodrug strategy has been developed recently (20,21,38). Sob-AM2, a methyl amide derivative of sobetirome, is an optimized prodrug that significantly increases delivery of sobetirome to the brain while at the same time decreasing the sobetirome blood and peripheral organ exposure (38).…”

“…We have also shown that the iCKO-Myrf mouse represents a compelling model for the evaluation of myelin repair agents in which CNS demyelination and remyelination can be correlated to clinical decline and recovery. Sobetirome, Sob-AM2 (38), and other recently developed sobetirome derivatives (20,21,52) are the only thyromimetics reported to date that distribute to the CNS from systemic administration, making this subset of selective TH agonists suitable for clinical evaluation in demyelinating diseases such as MS.…”

“…TH agonists, or thyromimetics, are a class of compounds that mimic T3 binding at the TH receptor (TR). Sobetirome is a clinical-stage thyromimetic devoid of the adverse effects associated with hyperthyroidism and unique among thyromimetics for its ability to cross the blood-brain barrier and distribute to the CNS from a systemic dose (20,21). Sobetirome has been shown to stimulate TH actions during brain development (22,23) and alter brain lipid biomarkers in a model of X-linked adrenoleukodystrophy (24).…”

Sobetirome and its Amide Prodrug Sob-AM2 Exert Thyromimetic Actions in Mct8-Deficient Brain

“…Sobetirome is a clinical stage molecule that has progressed into clinical trials for hyperlipidemia (37) and is currently in clinical development for X-linked adrenoleukodystrophy, an inborn error of metabolism affecting the CNS and adrenals (Clin-icalTrials.gov Identifier: NCT03196765). More recently, prodrugs of sobetirome have been developed with beneficial pharmacokinetic properties, including lower peripheral exposure and increased CNS distribution of sobetirome (38)(39)(40). Among these, an amide prodrug of sobetirome, Sob-AM2, leads to increased sobetirome concentrations across all brain regions, approximately ninefold higher than the parent drug with decreased peripheral sobetirome exposure.…”