A CNS-Targeting Prodrug Strategy for Nuclear Receptor Modulators

Abstract

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.

Thyroid hormone and thyromimetics inhibit myelin and axonal degeneration and oligodendrocyte loss in EAE

“…The TRβ selective thyroid hormone agonist sobetirome (Sob) (also called GC-1) lacks the systemic toxic effects of TH but retains its therapeutic benefits (Scanlan, 2010). To enhance the CNS effects of Sob, we previously developed and evaluated CNS-penetrating prodrugs, including Sob-AM2, that cross the blood brain barrier and within the CNS are hydrolyzed to produce high levels of Sob (Meinig et al, 2017(Meinig et al, , 2018Ferrara et al, 2017;Bárez-López et al, 2018;Ferrara and Scanlan, 2020). Compared to Sob, an equivalent bioavailable fraction of Sob-AM2 delivers more than ten times the thyromimetic exposure to the CNS while masking thyromimetic activity in the periphery, thus increasing therapeutic index (Meinig et al, 2018).…”

Large-scale genomic data-mining implicates dysregulated nuclear receptor-mediated signaling in mental illness

“…Upon activation, NRs facilitate fine-tuned transcriptional regulation of defined sets of promotor hormone response element (HRE)-containing target genes in a cell-, tissue-, and developmental-specific manner. In this way, NRs play essential roles in the developing and mature central nervous system (CNS) [41,42] and have crucial and diverse functions in many aspects of human metabolism, reproduction, inflammation, and physiology [41] . Consequently, NRs are highly intolerant to loss of function (LoF) mutations [43] , and genetic defects in at least 20 of the 48 NRs encoded by the human genome are associated with pathological states, including neurological disorders and mental illness [41,44] .…”

“…In this way, NRs play essential roles in the developing and mature central nervous system (CNS) [41,42] and have crucial and diverse functions in many aspects of human metabolism, reproduction, inflammation, and physiology [41] . Consequently, NRs are highly intolerant to loss of function (LoF) mutations [43] , and genetic defects in at least 20 of the 48 NRs encoded by the human genome are associated with pathological states, including neurological disorders and mental illness [41,44] . The latter is highlighted by the severe intellectual disability displayed by autism spectrum disorder (ASD) and epilepsy cases harboring LoF mutations in genes encoding retinoic acid receptor-related orphan receptors (RORA [45] and RORB [46] ).…”

“…Supporting an overall increased genetic risk load in NR transcriptional networks in mental illness, genetic variation in loci harboring NR coregulators has been reported in a range of PDs (see Supplementary Table 1 for a summary), and increased polygenic burden in retinoid and glucocorticoid biogenesis and signaling pathways has recently been associated with schizophrenia (SZ) and depression, respectively [18,61] . The importance of NR coregulator-mediated modulation of NR action has further been demonstrated by molecular genetic studies in preclinical models [41] , where genetic disruption to NR coregulators generally results in behavioral impairments and neurobiological alterations with translational relevance to PDs [55,[62][63][64][65][66][67][68][69] . Collectively, ample evidence implicates dysregulated NR-mediated signaling in the pathoetiology of mental illness, and it is thus conceivable that genetic vulnerability to NR-mediated signaling, in combination with their ligand-associated risk factors, collectively shapes the risk and clinical manifestation of PDs.…”

Thyroid hormone and thyromimetics inhibit myelin and axonal degeneration and oligodendrocyte loss in EAE

“…2017; Bárez-López et al . 2018; Ferrara and Scanlan 2020). Compared to Sob, an equivalent bioavailable fraction of Sob-AM2 delivers more than ten times the thyromimetic exposure to the CNS while masking thyromimetic activity in the periphery, thus increasing therapeutic index (Meinig et al 2018).…”