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While suppressing glycosphingolipid accumulation is the central strategy for treating peripheral symptoms of GD, there is no effective treatment for the central nervous system symptoms. As glycosphingolipid biosynthesis starts from ceramide glycosylation by glucosylceramide synthase (GCS), inhibiting GCS in the brain is a promising strategy for neurological GD. Herein, we discovered T\u2010036, a potent and brain\u2010penetrant GCS inhibitor with a unique chemical structure and binding property. T\u2010036 does not harbor an aliphatic amine moiety and has a noncompetitive inhibition mode to the substrates, unlike other known inhibitors. T\u2010036 exhibited sufficient exposure and a significant reduction of glucosylsphingolipids in the plasma and brain of the GD mouse model. Therefore, T\u2010036 could be a promising lead molecule for treating central nervous system symptoms of GD.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15492-fig-0006-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15492","type":"journal-article","created":{"date-parts":[[2021,8,16]],"date-time":"2021-08-16T15:06:25Z","timestamp":1629126385000},"page":"543-553","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A new brain\u2010penetrant glucosylceramide synthase inhibitor as potential Therapeutics for Gaucher disease"],"prefix":"10.1111","volume":"159","author":[{"given":"Takahiro","family":"Fujii","sequence":"first","affiliation":[{"name":"Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6110-7990","authenticated-orcid":false,"given":"Yuta","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Neuroscience Drug Discovery Unit, Research, Takeda Pharmaceutical Company Limited Fujisawa Kanagawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyuki","family":"Oki","sequence":"additional","affiliation":[{"name":"Discovery Biology, Discovery Science Axcelead Drug Discovery Partners, Inc. 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