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.

Yan Guo

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