Identification of pyrimidinyl piperazines as non-iminosugar glucocerebrosidase (GCase) pharmacological chaperones

Glucocerebrosidase (GCase) is a lysosomal enzyme encoded by the GBA1 gene, loss of function variants of which cause an autosomal recessive lysosomal storage disorder, Gaucher disease (GD). Heterozygous variants of GBA1 are also known as the strongest common genetic risk factor for Parkinson's disease (PD). Restoration of GCase enzymatic function using a pharmacological chaperone strategy is considered a promising therapeutic approach for PD and GD. We identified compound 4 as a GCase pharmacological chaperone with sub-micromolar activity from a high-throughput screening (HTS) campaign. Compound 4 was further optimised to ER-001230194 (compound 25). ER-001230194 shows improved ADME and physicochemical properties and therefore repre-sents a novel pharmacological chaperone with which to investigate GCase pharmacology further.

Automated summary

Glucocerebrosidase (GCase) is an enzyme encoded by the GBA1 gene, and its loss of function variants cause Gaucher disease (GD). Heterozygous variants of GBA1 are also the strongest common genetic risk factor for Parkinson's disease (PD). A compound with sub-micromolar activity was identified as a GCase pharmacological chaperone, and it was further optimized to a novel compound with improved ADME and physicochemical properties for investigating GCase pharmacology.