Synthesis inhibition is the basis for the treatment of type 1 Gaucher disease by 
the glucosylceramide synthase (GCS) inhibitor eliglustat tartrate. However, the 
extended use of eliglustat and related compounds for the treatment of 
glycosphingolipid storage diseases with CNS manifestations is limited by the 
lack of brain penetration of this drug. Property modeling around the 
D-threo-1-phenyl-2-decanoylamino-3-morpholino-propanol (PDMP) pharmacophore was 
employed in a search for compounds of comparable activity against the GCS but 
lacking P-glycoprotein (MDR1) recognition. Modifications of the carboxamide 
N-acyl group were made to lower total polar surface area and rotatable bond 
number. Compounds were screened for inhibition of GCS in crude enzyme and whole 
cell assays and for MDR1 substrate recognition. One analog, 
2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide 
(CCG-203586), was identified that inhibited GCS at low nanomolar concentrations 
with little to no apparent recognition by MDR1. Intraperitoneal administration 
of this compound to mice for 3 days resulted in a significant dose dependent 
decrease in brain glucosylceramide content, an effect not seen in mice dosed in 
parallel with eliglustat tartrate.