Takeda, Kunitoshi; Watanabe, Toru; Smith, James R; Vesey, David; Tiberghien, Nathalie; Lewis, Sian; Powney, Ben; ... Takle, Andrew K; + view all Takeda, Kunitoshi; Watanabe, Toru; Smith, James R; Vesey, David; Tiberghien, Nathalie; Lewis, Sian; Powney, Ben; Schapira, Anthony HV; Hoshikawa, Tamaki; Takle, Andrew K; - view fewer (2023) Identification of novel glucocerebrosidase chaperones by unexpected skeletal rearrangement reaction. Bioorganic & Medicinal Chemistry Letters , 96 , Article 129531. 10.1016/j.bmcl.2023.129531.

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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 C[sbnd]C 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 EC50 values as exemplified by compound 38 (EC50 = 0.14 μM).

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