Optimization of Eliglustat-Based Glucosylceramide Synthase Inhibitors as Substrate Reduction Therapy for Gaucher Disease Type 3

Abstract

There remain no approved therapies for rare but devastating neuronopathic glyocosphingolipid storage diseases, such as Sandhoff, Tay-Sachs, and Gaucher disease type 3. We previously reported initial optimization of the scaffold of eliglustat, an approved therapy for the peripheral symptoms of Gaucher disease type 1, to afford 2, which effected modest reductions in brain glucosylceramide (GlcCer) in normal mice at 60 mg/kg. The relatively poor pharmacokinetic properties and high Pgp-mediated efflux of 2 prompted further optimization of the scaffold. With a general objective of reducing topological polar surface area, and guided by multiple metabolite identification studies, we were successful at identifying 17 (CCG-222628), which achieves remarkably greater brain exposure in mice than 2. After demonstrating an over 60-fold improvement in potency over 2 at reducing brain GlcCer in normal mice, we compared 17 with Sanofi clinical candidate venglustat (Genz-682452) in the CBE mouse model of Gaucher disease type 3. At doses of 10 mg/kg, 17 and venglustat effected comparable reductions in both brain GlcCer and glucosylsphingosine. Importantly, 17 achieved these equivalent pharmacodynamic effects at significantly lower brain exposure than venglustat.

Neuroinflammation in neuronopathic Gaucher disease: Role of microglia and NK cells, biomarkers, and response to substrate reduction therapy

“…Previous studies in mice have suggested utility of brain permeant GCS inhibitor as treatment for neuronopathic GD but a clinical trial of miglustat (N-butyldeoxynojirimycin), an iminosugar, did not improve neurological end points in GD3 ( Schiffmann et al, 2008 ). Subsequently, more potent GCS inhibitors based on ceramide analogs have shown more promise in genetic nGD model and in chemically induced model ( Blumenreich et al, 2021 ; Cabrera-Salazar et al, 2012 ; Shayman, 2010 ; Wilson et al, 2020 ).…”

“…However, it is a relatively weak inhibitor of GCS with more potent inhibitory off-target effects ( Schiffmann et al, 2008 ). However, more specific and potent GCS inhibitors are showing early promise ( Schiffmann et al, 2020 ; Wilson et al, 2020 ).…”

Neuroinflammation in neuronopathic Gaucher disease: Role of microglia and NK cells

“…However, it is relatively weak inhibitor of GCS with more potent inhibitory off-target effects (Schiffmann et al, 2008). However, more specific and potent GCS inhibitors are showing early promise (Schiffmann, 2020; Wilson et al, 2020).…”

“…However, it is relatively weak inhibitor of GCS with more potent inhibitory off-target effects (Schiffmann et al, 2008). However, more specific and potent GCS inhibitors are showing early promise (Schiffmann, 2020;Wilson et al, 2020). (A) Quantitative analysis of total GluCer/GlcSph levels in Gba loxp/loxp Cx3cr1 Cre/wt mice and control mice (n=3 mice/group).…”

Lipids in Pathophysiology and Development of the Membrane Lipid Therapy: New Bioactive Lipids

“…Indeed, these mutations can provoke the deposition of α-synuclein in the brain due to changes in the composition of sphingolipids [259]. Different glucosylceramide synthase inhibitors, a key enzyme in the first step of the glycosphingolipid synthesis, are being tested to palliate the visceral and blood symptoms of GD [260,261]. Moreover, new drugs with the ability to cross the BBB are currently being tested to reduce the levels of the glycosphingolipids in the brain of patients with PD [262].…”