Glucocerebrosidase (GCase) is a lysosomal enzyme that metabolizes the glycolipids glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Loss-of-function mutations in GCase are the most prevalent genetic risk factor for Parkinson’s Disease (PD). Elevated glycolipid levels impair lysosomal function and accelerate formation of α-synuclein aggregates, a pathological hallmark of PD. Our therapeutic strategy was aimed at reducing GlcCer and GlcSph levels via development of glucosylceramide synthase inhibitors (GCSI’s) to enable restoration of lysosomal function and clearance of toxic phosphorylated α-synuclein aggregates. We have shown in preclinical studies in iPSC-derived human neurons that treatment with GCSi BZ1 reduced the accumulation of pathological α-synuclein and improved lysosomal function. Furthermore, a brain penetrant GCSi, GZ667161, has been shown to reduce central α-synuclein accumulation and attenuate cognitive impairment in a GBA-mutant mouse model. Prior to Sanofi’s disclosure of negative data from their Phase 2 MOVES-PD trial with venglustat, we focused on identifying a novel orally bioavailable and brain penetrant GCSi for the treatment of PD. Described in the talk is the discovery of a fused pyrazole urea series that was rapidly advanced through focused libraries, enabled by the development of synthetic methodology, to address the issues of off-target activity, potency and pharmacokinetics (PK). This talk will highlight the use of predictive in silico tools for optimization, including site-of-metabolism predictions to improve PK, the use of a literature pharmacophore model for selectivity against 5-HT3, and the retrospective analysis of hydrogen bond basicity calculations to rationalize improvements in transporter profiles. These efforts culminated in the rapid discovery of leads that show excellent potency and selectivity, low projected human doses, and low transporter susceptibility.

Accelerated discovery of CNS penetrant, low dose glucosylceramide synthase inhibitors for the treatment of Parkinson’s disease

ACS Spring 2022

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