Mechanism of Brain Targeting by Dexibuprofen Prodrugs Modified with Ethanolamine-Related Structures

Abstract

The first molecular insights into how prodrugs modified with ethanolamine-related structures target the brain were generated using an in vitro BBB model and in situ perfusion technique. Prodrugs were delivered safely and efficiently to the brain through tight interaction with the anionic membrane of brain capillary endothelial cells, observed as a shift in zeta potential, followed by uptake into the cells. Prodrugs III and IV carrying primary and secondary amine modifications appeared to enter the brain via energyindependent passive diffusion. In contrast, besides the passive diffusion, prodrugs I and II carrying tertiary amine modifications also appeared to enter via an active process that was energy and pH dependent but was independent of sodium or membrane potential. This active process involved, at least in part, the pyrilamine-sensitive H + /OC antiporter, for which the N,N-diethyl-based compound II showed a much lower affinity than the N,N-dimethyl-based compound I, likely due to steric hindrance. These new insights into brain-targeting mechanisms may help guide efforts to design new prodrugs.

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

“…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.…”

“…These findings suggest that a similar rearrangement may occur in vivo with the previously reported dexibuprofen enthanolamine prodrugs that inspired our efforts with sobetirome. 19, 20 This previous work reported an ethanolamino ester, N -alkyl ethanolamino ester, and an N , N -dialkyl ethanolamino ester derivative, of which it seems likely that the former two could undergo a similar rearrangement to the corresponding amides. However, their results run counter to that which we observe, where the bona fide ester in their series ( N , N -dialkyl ethanolamino derivative) displayed the best BBB permeability.…”

Sobetirome prodrug esters with enhanced blood–brain barrier permeability

“…Ethanolamine moieties, when attached to carboxylic acids, have been shown previously to enhance the brain/serum ratios of dexibuprofen. 26-27 The ethanolamine sobetirome prodrug synthesis was started in a similar manner to 9 except Boc-ethanolamine (Boc = tert -butyloxycarbonyl) was used (Scheme 3). The protected ethanolamine intermediate ( 10 ) was then subjected to benzyl deprotection conditions, followed by HCl (ethyl acetate) to remove the Boc residue resulting in 11 in a 37% overall yield for the three steps.…”

“…3d), although some of these modifications decreased blood levels of sobetirome resulting in an increased brain/blood ratio (data not shown). The dimethylethanolamine ( 19a ) was previously shown to be more effective than ethanolamine 26 at increasing BBB permeability when esterified to dexibuprofen, 27 a different carboxylic acid containing drug, but in the context of sobetirome 19 is significantly less effective than 11 and offers no BBB permeability enhancement over sobetirome itself. Likewise, the 2-morpholinoethyl ester 9 that contains a tertiary ethanolamine did not significantly increase sobetirome brain levels (Fig.…”

“…However, the prodrugs were prepared and administered as esters in accord with the previous work that demonstrated increased BBB permeability with ethanolamine esters of carboxylate drugs. 26,27 Future mechanistic studies to elucidate how prodrug 11 accesses the CNS in vivo are warranted.…”