title: Property-based design of a glucosylceramide synthase inhibitor that reduces glucosylceramide in the brain.
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.
authors: Vahlteich Medicinal Chemistry Core - Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA. sdlarsen@umich.edu
authors: Scott D
authors: SD
authors: Larsen
authors: Michael W
authors: MW
authors: Wilson
authors: Akira
authors: A
authors: Abe
authors: Liming
authors: L
authors: Shu
authors: Christopher H
authors: CH
authors: George
authors: Paul
authors: P
authors: Kirchhoff
authors: H D Hollis
authors: HD
authors: Showalter
authors: Jianming
authors: J
authors: Xiang
authors: Richard F
authors: RF
authors: Keep
authors: James A
authors: JA
authors: Shayman
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004146:Dioxanes / Q000138:chemical synthesis / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005963:Glucosylceramides / Q000378:metabolism*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D007189:Indans / Q000138:chemical synthesis / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000737:chemistry; D014747:Vinblastine / Q000493:pharmacokinetics
chemical_list: C574542:2-(2,3-dihydro-1H-inden-2-yl)-N-(1-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)acetamide; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004146:Dioxanes; D004791:Enzyme Inhibitors; D005963:Glucosylceramides; D007189:Indans; D009025:Morpholines; D014747:Vinblastine; C033110:RV 538; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase