1. Identification of novel glucocerebrosidase chaperones by unexpected skeletal rearrangement reaction.
- Author
-
Takeda K, Watanabe T, Smith JR, Vesey D, Tiberghien N, Lewis S, Powney B, Schapira AHV, Hoshikawa T, and Takle AK
- Subjects
- Humans, Glucosylceramidase genetics, Mutation, Molecular Chaperones, Parkinson Disease, Gaucher Disease drug therapy
- Abstract
Compound 5 was identified from a high-throughput screening campaign as a small molecule pharmacological chaperone of glucocerebrocidase (GCase), a lysosomal hydrolase encoded by the GBA1 gene, variants of which are associated with Gaucher disease and Parkinson's disease. Further investigations revealed that compound 5 was slowly transformed into a regio-isomeric compound (6) in PBS buffer, plausibly via a ring-opening at hemiaminal moiety accompanied by subsequent intramolecular CC bond formation. Utilising this unexpected skeletal rearrangement reaction, a series of compound 6 analogues was synthesized which yielded multiple potent GCase pharmacological chaperones with sub-micromolar EC
50 values as exemplified by compound 38 (EC50 = 0.14 μM)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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