4.7 Article

Glucocerebrosidase (GCase) activity modulation by 2-alkyl trihydroxypiperidines: Inhibition and pharmacological chaperoning

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BIOORGANIC CHEMISTRY
卷 98, 期 -, 页码 -

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ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2020.103740

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  1. Fondazione Cassa di Risparmio di Pistoia e Pescia (Bando Giovani@Ricerca scientifica 2017)
  2. MIUR-Italy (Progetto Dipartimenti di Eccellenza 2018-2022)
  3. Universita di Firenze
  4. Fondazione CR Firenze [2016/0845, 2018.0942]
  5. Ministerio de Economia y Competitividad of Spain [CTQ2016-77270-R]

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The enzyme glucocerebrosidase (GCase) has become an important therapeutic target due to its involvement in pathological disorders consequent to enzyme deficiency, such as the lysosomal storage Gaucher disease (GD) and the neurological Parkinson disease (PD). Pharmacological chaperones (PCs) are small compounds able to stabilize enzymes when used at sub-inhibitory concentrations, thus rescuing enzyme activity. We report the stereodivergent synthesis of trihydroxypiperidines alkylated at C-2 with both configurations, by means of the stereoselective addition of Grignard reagents to a carbohydrate-derived nitrone in the presence or absence of Lewis acids. All the target compounds behave as good GCase inhibitors, with IC50 in the micromolar range. Moreover, compound 11a behaves as a PC in fibroblasts derived from Gaucher patients bearing the N370/RecNcil mutation and the homozygous L444P mutation, rescuing the activity of the deficient enzyme by up to 1.9-and 1.8-fold, respectively. Rescues of 1.2-1.4-fold were also observed in wild-type fibroblasts, which is important for targeting sporadic forms of PD.

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