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

Hoshikawa, T; Watanabe, T; Kotake, M; Tiberghien, N; Woo, CK; Lewis, S; Briston, T; ... Takle, AK; + view all (2023) Identification of pyrimidinyl piperazines as non-iminosugar glucocerebrosidase (GCase) pharmacological chaperones. Bioorganic and Medicinal Chemistry Letters , 81 , Article 129130. 10.1016/j.bmcl.2023.129130. Green open access

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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.

Type: Article
Title: Identification of pyrimidinyl piperazines as non-iminosugar glucocerebrosidase (GCase) pharmacological chaperones
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.bmcl.2023.129130
Publisher version: https://doi.org/10.1016/j.bmcl.2023.129130
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Gaucher disease, Glucocerebrosidase, Parkinson’s disease, Pharmacological Chaperone
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10164281
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