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. 2020 Oct 21;11(20):3464-3473.
doi: 10.1021/acschemneuro.0c00558. Epub 2020 Oct 9.

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

Michael W Wilson  1 , Liming Shu  2 , Vania Hinkovska-Galcheva  2 , Yafei Jin  1 , Walajapet Rajeswaran  1 , Akira Abe  2 , Ting Zhao  3 , Ruijuan Luo  3 , Lu Wang  3 , Bo Wen  3 , Benjamin Liou  4 , Venette Fannin  4 , Duxin Sun  3 , Ying Sun  4 , James A Shayman  2 , Scott D Larsen  1   5
Affiliations

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

Michael W Wilson et al. ACS Chem Neurosci. .

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.

Keywords: Gaucher disease; Glucosylceramide synthase; blood−brain barrier; eliglustat tartrate.

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Figures

Figure 1.
Figure 1.
Lead glucosylceramide synthase inhibitors.
Figure 2.
Figure 2.
Identification of metabolites of 2 formed by incubation with mouse liver microsomes.
Figure 3.
Figure 3.
Identification of metabolites of 15 formed by incubation with mouse liver microsomes.
Figure 4.
Figure 4.
Identification of metabolites of 17 formed by incubation with mouse liver microsomes.
Figure 5.
Figure 5.
Effect of 17 on brain glucosylceramide in wild-type mice. Compound or vehicle was administered IP at the indicated doses for 3 days. Data shown is a merge of two separate dose response experiments (Exp 1: 30, 10, 1 mg/kg; Exp 2: 1.0, 0.30, 0.10, 0.03 mg/kg). ns: change is not significant.
Figure 6.
Figure 6.
Effect of 17 (CCG-222628) on brain glycosphingolipids in CBE mice. Eliglustat and venglustat (3, Genz-682452) were included as comparators. Compounds were all coadministered IP at a dose of 10 mg/kg qd for 14 days.
Scheme 1.
Scheme 1.
Synthetic Route to New Eliglustat Analoguesa aReagents and conditions: (a) (S)-5-phenylmorpholin-2-one, toluene, azeotropic reflux, 24 h; (b) R3R4NH, heat; (c) aq HCl; (d) LiAlH4; (e) BH3; (f) H2, Pd/C; (g) R5CH2COO-Suc; (h) R5CH2COOH, EDC.
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