Identification of pyrimidinyl piperazines as non-iminosugar glucocerebrosidase (GCase) pharmacological chaperones
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Updated: Aug 14, 2025

In Vitro Enzyme Measurement to Test Pharmacological Chaperone Responsiveness in Fabry and Pompe Disease
Published on: December 20, 2017
Tamaki Hoshikawa1, Toru Watanabe1, Makoto Kotake1
1Hatfield Research Laboratories, Eisai Ltd., Hatfield AL10 9SN, United Kingdom.
Abstract:
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 represents a novel pharmacological chaperone with which to investigate GCase pharmacology further.
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