Sobetirome prodrug esters with enhanced blood–brain barrier permeability

Abstract

There is currently great interest in developing drugs that stimulate myelin repair for use in demyelinating diseases such as multiple sclerosis. Thyroid hormone plays a key role in stimulating myelination during development and also controls the expression of important genes involved in myelin repair in adults. Because endogenous thyroid hormone in excess lacks a generally useful therapeutic index, it is not used clinically for indications other than hormone replacement; however, selective thyromimetics such as sobetirome offer a therapeutic alternative. Sobetirome is the only clinical-stage thyromimetic that is known to cross the blood-brain-barrier (BBB) and we endeavored to increase the BBB permeability of sobetirome using a prodrug strategy. Ester prodrugs of sobetirome were prepared based on literature reports of improved BBB permeability with other carboxylic acid containing drugs and BBB permeability was assessed in vivo. One sobetirome prodrug, ethanolamine ester 11, was found to distribute more sobetirome to the brain compared to an equimolar peripheral dose of unmodified sobetirome. In addition to enhanced brain levels, prodrug 11 displayed lower sobetirome blood levels and a brain/serum ratio that was larger than that of unmodified sobetirome. Thus, these data indicate that an ester prodrug strategy applied to sobetirome can deliver increased concentrations of the active drug to the central nervous system (CNS), which may prove useful in the treatment of CNS disorders.

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

“…Following prodrug 6 , the next highest brain/serum ratio is that for prodrug 3 with a value of 0.5, which is ~13-fold higher than the brain/serum ratio of sobetirome, and ~7-fold higher than previously reported 2 . 18 From this biodistribution study, it appears that the prodrugs which can undergo this intramolecular ester-to-amide rearrangement of their promoities display the desired PK-ADME properties for CNS distribution, suggesting that amide prodrugs of sobetirome are the pharmacologically active species of interest. This was confirmed by analyzing prodrug 3 synthesized as an ester (3a) side-by-side with the deliberately prepared amide of 3 (3b) , which gave statistically identical brain levels and brain/serum ratios at equimolar doses (see Supporting Information).…”

“…In line with the recently reported successful application of an ethanolamine-based ester prodrug of sobetirome 18 and ethanolamine-based ester prodrugs of dexibuprofen, 19, 20 a drug with structural similarities to sobetirome, a new series of ethanolamine-derived prodrugs of sobetirome were synthesized in an effort to expand upon these findings and improve their pharmacokinetic properties regarding CNS distribution (Scheme 1). Derivatization of the ethanolamine moiety within the series explores varying aspects of steric and electronic parameters with subtle differences in lipophilicity.…”

“…22 Generation of the acid chloride of phenol-benzylated sobetirome (Scheme 1, left) is accomplished by treating phenol-benzylated sobetirome with oxalyl chloride in the presence of a catalytic amount of DMF. 18, 23 Coupling of the phenol-protected sobetirome acid chloride with N -protected amino alcohols occurs readily in the presence of DMAP in heated THF. Global deprotection of benzyl ether, N -Cbz, and N -benzyl protected fragments follows with treatment of the protected precursors with 10% Pd/C and triethylsilane in THF/MeOH.…”

“…Prodrug 3 delivers 3.6-fold more sobetirome to the brain than an equimolar dose of unmodified sobetirome, and its levels are 1.7-fold higher than the previously reported ethanolamine-derived prodrug of sobetirome 2 in a side-by-side comparison. 18 In addition to BBB penetration, an ideal prodrug would be stable in blood and limit exposure of the parent drug in peripheral tissues. Most prodrugs in this series displayed higher brain/serum ratios than the control dose of sobetirome.…”

“…Recently, an in vivo study evaluating the brain exposure of ester-based prodrugs of sobetirome confirmed this strategy to be effective. 18 In this study, a particular ester derivative, an ethanolamino ester (2) , was found to have the greatest CNS penetration with minimized peripheral exposure of the parent drug. Here we report a new series of prodrugs that feature improved CNS distribution compared to the originally reported ethanolamino ester and, in the process, it was discovered that these ester promoieties undergo an intramolecular rearrangement to form the corresponding amides, which were found to be the pharmacologically active forms of the prodrugs.…”