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.
Subject(s)
Gaucher Disease , Parkinson Disease , Humans , Glucosylceramidase/genetics , Mutation , Parkinson Disease/drug therapy , Gaucher Disease/drug therapy , LysosomesABSTRACT
A novel series of methyl ester-terminated C8-linked pyrrolobenzodiazepine (PBD)-poly(N-methylpyrrole) conjugates (50a-f) has been synthesized and their DNA interaction evaluated by thermal denaturation, DNA footprinting, and in vitro transcription stop assays. The synergistic effect of attaching a PBD unit to a polypyrrole fragment is illustrated by the large increase in DNA binding affinity (up to 50-fold) compared to the individual PBD and pyrrole components. 50a-f were found to bind mainly to identical DNA sequences but with apparent binding site widths increasing with molecular length and the majority of sites conforming to the consensus motif 5'-XGXWz (z = 3 +/- 1; W = A or T; X = any base but preferably a purine). They also provided robust sequence-selective blockade of transcription at sites corresponding approximately to their DNA footprints. 50a-f were shown to have good cellular/nuclear penetration properties, and a degree of correlation between cytotoxicity and DNA-binding affinity was observed.
Subject(s)
Antineoplastic Agents/chemical synthesis , Benzodiazepines/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Pyrroles/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Benzodiazepines/chemistry , Benzodiazepines/pharmacology , Cell Line, Tumor , Cell Membrane Permeability , Cell Nucleus/metabolism , DNA/chemistry , DNA Footprinting , Drug Screening Assays, Antitumor , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Models, Molecular , Nucleic Acid Denaturation , Permeability , Pyrroles/chemistry , Pyrroles/pharmacology , Stereoisomerism , Structure-Activity Relationship , Transcription, GeneticABSTRACT
A N-derivatized 3-dimethylaminopropyloxypyrazole library was prepared using solution-phase parallel synthesis. The library was designed using physicochemical constraints designed to remove non-membrane-permeable molecules. Cupric acetate-mediated N-arylation with aryl boronic acids proceeded regioselectively to form the N-2-substituted derivatives. The presence of the 3-dimethylaminopropyloxy group was found to completely control the regioselectivity of the arylation. Presence of a dimethylaminoethyloxy or dimethylaminobutyloxy group gave a lesser degree of regioselectivity. The scope of the method as applied to library synthesis is discussed.