Structure–Activity Relationships of Central Nervous System Penetration by Fatty Acid Amide Hydrolase (FAAH)-Targeted Thyromimetic Prodrugs

Meinig, J. Matthew; Ferrara, Skylar J.; Banerji, Tapasree; Banerji, Tania; Sanford-Crane, Hannah; Bourdette, Dennis; Scanlan, Thomas S.

doi:10.1021/acsmedchemlett.8b00501

Cited by 11 publications

(20 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.)…”

Section: Discussionsupporting

confidence: 79%

“…We observed significant improvements in rotarod performance and recovery in the iCKO-Myrf model (Figures 4 and 8). Although Sob-AM2 treatment increases sobetirome CNS exposure compared with an equivalent dose of sobetirome by virtue of FAAH activity in the CNS, we have recently found that the magnitude of this distribution depends on the route of administration (42). In addition to being expressed in the CNS, FAAH is also present at high levels in the gastrointestinal tract, especially in rodents (43).…”

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

Myelin repair stimulated by CNS-selective thyroid hormone action

Hartley¹,

Banerji²,

Tagge³

et al. 2019

JCI Insight

Self Cite

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 94%

Myelin repair stimulated by CNS-selective thyroid hormone action

Hartley¹,

Banerji²,

Tagge³

et al. 2019

JCI Insight

Self Cite

View full text Add to dashboard Cite

“…The oral bioavailability of Sob-AM2 is 20% in mice, while that of sobetirome is >90% (Meinig et al, 2019). To confirm that chow administration of either drug provides the anticipated sobetirome levels in vivo, sobetirome concentrations in serum and brain were measured in mice administered chow for 12 weeks at doses of 80 µg/kg sobetirome or 84 µg/kg Sob-AM2 (Devereaux et al, 2018;Placzek et al, 2016;Placzek and Scanlan, 2015).…”

Section: Sob-am2 Lowered Peripheral and Central Vlcfas After Oral Admmentioning

confidence: 99%

“…This study was designed to address this question by using two different strategies to increase thyroid hormone action in the CNS. The first strategy employed Sob-AM2, an amide prodrug derivative of sobetirome that improves distribution of sobetirome to the CNS by 10-fold and increases the brain-to-serum ratio by 60-fold Meinig et al, 2017Meinig et al, , 2019Placzek et al, 2016). Sob-AM2 is converted to sobetirome via hydrolysis by fatty acid amide hydrolase (FAAH), which is highly expressed in the CNS .…”

Section: Introductionmentioning

confidence: 99%

Pharmacological complementation remedies an inborn error of lipid metabolism

Hartley

Shokat

DeBell

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

X-linked adrenoleukodystrophy (X-ALD) is a genetic disease involving loss of function of the peroxisomal transporter ABCD1, resulting in an inappropriate increase in very long chain fatty acid (VLCFA) concentrations throughout the body. Elevated levels of VLCFAs in the central nervous system (CNS) cause demyelination and axonal degeneration, leading to severe neurological deficits. Sobetirome, a potent thyroid hormone agonist, and other thyromimetics have been shown to lower VLCFA levels. In this study, two pharmacological strategies for enhancing the effects of thyromimetics in the brain were tested. First, a CNS-selective thyromimetic prodrug was used to increase thyromimetic drug exposure in the CNS. Second, thyroid hormone and the thyromimetic were co-administered to increase total thyroid hormone agonism in the CNS. These strategies lowered VLCFAs by up to 60% in the periphery. In the brain and spinal cord, C26/C22 was lowered by 15-20% and C26-LPC by 25-30% in the brain and ~40% in the spinal cord. Co-administration of thyroid hormone with sobetirome led to enhanced VLCFA lowering in the periphery compared to sobetirome alone but did not produce greater lowering in the CNS. The extent of lowering in the brain was limited by a mechanistic threshold related to slow turnover kinetics, which increased thyroid hormone action could not overcome. These findings provide evidence that CNS-penetrating thyromimetics can lower VLCFAs in peripheral organs in addition to the brain and spinal cord, thereby correcting the lipid abnormality associated with X-ALD. Keywordsthyroid hormone, thyromimetics, prodrugs, X-linked adrenoleukodystrophy, demyelination, very long chain fatty acids, myelin lipids, CNS lipids, inborn error of metabolism

show abstract

“…15 By targeting this specific enzyme, the prodrug remains masked in peripheral circulation and devoid of receptor activity. 11 The N-methyl amide of sobetirome proved to be the optimal amide for delivering the most sobetirome to the CNS from a systemic dose while at the same time minimizing the peripheral conversion of prodrug to parent drug. 11 However, an open question remained as to whether this prodrug strategy could be successfully employed for other carboxylate drugs that may have therapeutic applications in the CNS.…”

Section: Introductionmentioning

confidence: 99%

A CNS-Targeting Prodrug Strategy for Nuclear Receptor Modulators

Ferrara

Scanlan

2020

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

The blood-brain barrier is a major impediment for targeted central nervous system (CNS) therapeutics, especially with carboxylic acid-containing drugs. Nuclear receptors modulators, which often feature carboxylic acid motifs for target engagement, have emerged as a class of potentially powerful therapeutics for neurodegenerative CNS diseases. Herein is described a prodrug strategy which directs the biodistribution of parent drug nuclear receptor modulators into the CNS while masking them as functional receptor ligands in the periphery. This prodrug strategy targets a specific amidase, fatty-acid amide hydrolase (FAAH), an enzyme with enriched expression in the CNS. Cleavage of the prodrugs by FAAH in the CNS substantially increases brain exposure and brain-to-serum ratios (Kp), with increases up to ~100-fold compared to the Kp of the systemically administered parent drug. Structure-activity relationships reveal that drug-like molecules with a linear shape are the best FAAH substrates, and comparisons of CNS vs peripheral drug-induced pharmacodynamics validate the CNS-selective distribution. Our results demonstrate that this prodrug strategy can be generalized to a variety of carboxylic acid-containing drug structures that satisfy the structural requirements of blood-brain barrier diffusion and FAAH substrate recognition.

show abstract

Structure–Activity Relationships of Central Nervous System Penetration by Fatty Acid Amide Hydrolase (FAAH)-Targeted Thyromimetic Prodrugs

Cited by 11 publications

References 32 publications

Myelin repair stimulated by CNS-selective thyroid hormone action

Myelin repair stimulated by CNS-selective thyroid hormone action

Pharmacological complementation remedies an inborn error of lipid metabolism

A CNS-Targeting Prodrug Strategy for Nuclear Receptor Modulators

Contact Info

Product

Resources

About