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 pathological α-synuclein aggregates. In a recent publication, a brain penetrant glucosylceramide synthase inhibitor (GCSi), GZ667161, has been shown to reduce central α-synuclein accumulations and attenuate cognitive impairment in a GBA-mutant mouse model (PNAS, 2017, 114, 2699). Our internal preclinical studies in iPSC-derived human neurons further corroborated these findings (Neurobiol. Dis. 2021, 159, 105507). As a result, our therapeutic strategy was aimed at resolving GlcCer and GlcSph elevations via development of GCSi to enable restoration of lysosomal function and clearance of toxic phosphorylated α-synuclein aggregates. This presentation will detail our discovery efforts to identify a novel brain penetrant GCSi for the treatment of PD. Discovery and optimization of a pyrimidine series was expedited by data-rich design cycles through integration of predictive in silico tools, high-throughput experimentation (HTE) capabilities, rapid expansion of chemical diversity via nano-scale direct-to-biology (DtB) libraries, and development of robust chemistry platforms to enable efficient late-stage structure-activity relationship (SAR) exploration in a library format (Org. Lett. 2021, 23, 1996). Cross-functional collaborative efforts culminated in the discovery of a lead series that shows excellent potency and selectivity, good pharmacokinetic (PK) profile, low transporter susceptibility, and high levels of CNS exposure.

Discovery of glucosylceramide synthase inhibitors for the treatment of Parkinson’s disease through integration of hight-throughput experimentation and informatics

ACS Spring 2022

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