No 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.

No abstract

No abstract

A lead-lead chlorofluoride electrode has been used to determine fluoride ion activities, aF-, in 0-6 M aqueous HF. Our data show that aF- increases, passes through a maximum and then decreases with increasing HF concentration. The conductivities of concentrated HF- water mixtures have also been measured. Both the conductometric and potentiometric data are used in the development of a quantitative model of the equilibria existing between fluoride ions and HF molecules in the solutions studied. The data support the view that the ions (HF)2F-, (HF)3F- and (HF)4F- are important species in moderately concentrated aqueous HF.