Photoredox-based late-stage functionalization in SAR study for in vivo potent glucosylceramide synthase inhibitor

Glucosylceramide synthase (GCS) has drawn much attention as an attractive protein target in the disease pathways of Parkinson's Disease (PD) and lysosomal storage disorders, such as Gaucher's Disease (GD). In previous our study, T-036 and its analogue, 2a, were discovered as novel GCS inhibitors. To further improve activity of this chemical series, SAR was investigated on the fused pyridyl ring core of 2a by employing a photoredox reaction that significantly reduced synthetic demand. Herein, we successfully applied the decarboxylation C-H alkylation photoredox reaction to introduce a wide variety of substituents at the 6-position of the fused pyridine core scaffold. This quick SAR acquisition facilitated the swift identification of the potent GCS inhibitors 2b (IC₅₀ = 5.9 nM) and 2g (IC₅₀ = 3.6 nM). Moreover, 2b exhibited superior in vivo potency to that of our previously reported lead compound, T-036.