posted on 2023-12-21, 18:03authored byH. 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. Our strategy involved
the use of predicted volume ligand efficiency to advance compounds
with greater potential for low human doses down our screening funnel.
We also applied minimized electrostatic potentials (Vmin) calculations for hydrogen bond acceptor sites to
rationalize P-gp SAR. Together, our strategies enabled the alignment
of a lower human dose with reduced P-gp efflux, and favorable PXR
selectivity for the discovery of compound 12.