Property-based design of a glucosylceramide synthase inhibitor that reduces glucosylceramide in the brain

Scott D Larsen,Michael W Wilson,Akira Abe,Liming Shu,Christopher H George,Paul Kirchhoff,H D Hollis Showalter,Jianming Xiang,Richard F Keep,James A Shayman

doi:10.1194/jlr.m021261

Scott D Larsen, Michael W Wilson + Show 8 more

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https://doi.org/10.1194/jlr.m021261

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Abstract

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.

Highlights

Synthesis inhibition is the basis for the treatment of type 1 Gaucher disease by the glucosylceramide synthase (GCS) inhibitor eliglustat tartrate
We report on the design and synthesis of a series of PDMP analogs that are active against GCS, the evaluation of these compounds in in vitro models of MDR1 transport, and the identification of a novel analog that inhibits glucosylceramide (GlcCer) synthesis in both brain and peripheral organs
The GlcCer content of WT- and MDR1-MDCKII cells was measured as a function of inhibitor concentration to confirm that eliglustat tartrate (3a) was a substrate for the MDR1 transporter (Fig. 2A)

Summary

Introduction

Synthesis inhibition is the basis for the treatment of type 1 Gaucher disease by the glucosylceramide synthase (GCS) inhibitor eliglustat tartrate. Property modeling around the D-threo-1-phenyl-2-decanoylamino3-morpholino-propanol (PDMP) pharmacophore was employed in a search for compounds of comparable activity against the GCS but lacking P-glycoprotein (MDR1) recognition. Compounds were screened for inhibition of GCS in crude enzyme and whole cell assays and for MDR1 substrate recognition. 2-(2,3-dihydro-1H-inden-2-yl)-N((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy3-(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.—Larsen, S.

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