H Marie Loughran, Kathy M Schirripa, Anthony J Roecker, Michael J Breslin, Ling Tong, Kerry L Fillgrove, Yuhsin Kuo, Kelly Bleasby, Hannah Collier, Michael D Altman, Melissa C Ford, Justin A Newman, Robert E Drolet, Mali Cosden, Sarah Jinn, Rosemarie B Flick, Xiaomei Liu, Christina Minnick, Marla L Watt, Wei Lemaire, Christine Burlein, Gregory C Adam, Lauren A Austin, Jacob N Marcus, Sean M Smith, Mark E Fraley
Inhibition of glucosylceramide synthase (GCS) has been proposed as a therapeutic strategy for the treatment of Parkinson's Disease (PD), particularly in patients where glycosphingolipid accumulation and lysosomal impairment are thought to be contributing to disease progression. Herein, we report the late-stage optimization of an orally bioavailable and CNS penetrant isoindolinone class of GCS inhibitors. Starting from advanced lead 1 , we describe efforts to identify an improved compound with a lower human dose projection, minimal P-glycoprotein (P-gp) efflux, and acceptable pregnane X receptor (PXR) profile through fluorine substitution...
January 11, 2024: ACS Medicinal Chemistry Letters