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 <b>2</b>, 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 <b>2</b> 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 <b>17</b> (CCG-222628), which achieves remarkably greater brain exposure in mice than <b>2</b>. After demonstrating an over 60-fold improvement in potency over <b>2</b> at reducing brain GlcCer in normal mice, we compared <b>17</b> with Sanofi clinical candidate venglustat (Genz-682452) in the CBE mouse model of Gaucher disease type 3. At doses of 10 mg/kg, <b>17</b> and venglustat effected comparable reductions in both brain GlcCer and glucosylsphingosine. Importantly, <b>17</b> achieved these equivalent pharmacodynamic effects at significantly lower brain exposure than venglustat.