Novel compounds that reverse the disease phenotype in Type 2 Gaucher disease patient-derived cells.

Novel compounds that reverse the disease phenotype in Type 2 Gaucher disease patient-derived cells.
Bioorg Med Chem Lett. 2019 Nov 11;:126806
Authors: Childers W, Fan R, Martinez R, Colussi DJ, Melenski E, Liu Y, Gordon J, Abou-Gharbia M, Jacobson MA
Abstract
Gaucher disease (GD) results from inherited mutations in the lysosomal enzyme β-glucocerobrosidase (GCase). Currently available treatment options for Type 1 GD are not efficacious for treating neuronopathic Type 2 and 3 GD due to their inability to cross the blood-brain barrier. In an effort to identify small molecules which could be optimized for CNS penetration we identified tamoxifen from a high throughput phenotypic screen on Type 2 GD patient-derived fibroblasts which reversed the disease phenotype. Structure activity studies around this scaffold led to novel molecules that displayed improved potency, efficacy and reduced estrogenic/antiestrogenic activity compared to the original hits. Here we present the design, synthesis and structure activity relationships that led to the lead molecule Compound 31.
PMID: 31757667 [PubMed - as supplied by publisher]

Source: Bioorganic and Medicinal Chemistry Letters - November 10, 2019 Category: Chemistry Authors: Childers W, Fan R, Martinez R, Colussi DJ, Melenski E, Liu Y, Gordon J, Abou-Gharbia M, Jacobson MA Tags: Bioorg Med Chem Lett Source Type: research