Article: Pyrazole Ureas as Low Dose, CNS Penetrant Glucosylceramide Synthase Inhibitors for the Treatment of Parkinson's Disease.
ACS medicinal chemistry letters
2023 Volume 14, Issue 2, Page(s) 146–155
Abstract: Parkinson's disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme ... ...
| Abstract | Parkinson's disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme glucosylcerebrosidase, are a major genetic risk factor for the development of Parkinson's disease potentially through the accumulation of glucosylceramide and glucosylsphingosine in the CNS. A therapeutic strategy to reduce glycosphingolipid accumulation in the CNS would entail inhibition of the enzyme responsible for their synthesis, glucosylceramide synthase (GCS). Herein, we report the optimization of a bicyclic pyrazole amide GCS inhibitor discovered through HTS to low dose, oral, CNS penetrant, bicyclic pyrazole urea GCSi's with |
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| Language | English |
| Publishing date | 2023-01-12 |
| Publishing country | United States |
| Document type | Journal Article |
| ISSN | 1948-5875 |
| ISSN | 1948-5875 |
| DOI | 10.1021/acsmedchemlett.2c00441 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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