Salicylic acid derivatives useful as glucocerebrosidase activators
Inventors
Marugan, Juan Jose • Zheng, Wei • Patnaik, Samarjit • Southall, Noel • Sidransky, Ellen • Goldin, Ehud • Westbroek, Wendy • Aflaki, Elma • Rogers, Steven Andrew • Schoenen, Frank John
Assignees
University of Kansas • US Department of Health and Human Services
Publication Number
US-9464035-B2
Publication Date
2016-10-11
Expiration Date
2033-03-15
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Abstract
Compounds of Formula (I) and the pharmaceutically acceptable salts thereof are disclosed. The variables. R1-R13, m, n, o, and p are disclosed herein. The compounds are useful for treating Gaucher disease and inhibiting the onset of Gaucher disease symptoms in a patient having a GBA gene mutation and for treating Parkinson's disease. Pharmaceutical compositions containing compounds of Formula (I) and methods of treatment comprising administering compounds of Formula (I) are also disclosed.
Core Innovation
The invention relates to compounds of Formula (I), which are substituted salicylic acid derivatives and their pharmaceutically acceptable salts. These compounds are disclosed as useful for treating Gaucher disease, preventing or reducing symptoms of Gaucher disease in patients having a GBA gene mutation, and treating Parkinson's disease. Pharmaceutical compositions containing these compounds and methods of treatment comprising administering them are also provided.
Gaucher disease is caused by inherited mutations in the GBA gene, resulting in reduced activity of the enzyme glucocerebrosidase (GCase). This reduction leads to the accumulation of glucocerebroside inside cells, causing various symptoms including enlarged spleen and liver, anemia, neurodegeneration, and bone disease. Existing treatments such as enzyme replacement therapy and substrate reduction therapy are costly, and prior molecular chaperone approaches like isofagomine failed to reduce visceral symptoms despite increasing GCase levels. Consequently, there was an unmet need for novel chaperone therapies that effectively activate GCase without inhibiting its enzymatic activity.
The compounds of the present invention fulfill this need by activating, rather than inhibiting, glucocerebrosidase. They are chemically distinct from iminosugars previously described as chaperones and may exhibit selectivity against other glycosidases. The activation is proposed to assist the misfolded enzyme's proper folding and trafficking from the endoplasmic reticulum to lysosomes, thereby increasing active enzyme levels and reducing pathological lipid accumulation.
Claims Coverage
The patent includes multiple claims, with one independent claim and others that are dependent variations. The main inventive features involve the specific chemical structure of the compounds, their pharmaceutically acceptable salts, and their use in treatment methods.
Compound of Formula (I) and its pharmaceutically acceptable salts
A compound or pharmaceutically acceptable salt thereof having the specified Formula (I) with defined substituents and parameters including m, n, o, p, and R1-R13, which encompass substitutions such as halogen, alkyl, alkoxy, amino groups, and heterocycles, providing a novel chemical structure group.
Specific substitutions and embodiments of the compound
Preferred embodiments define particular substituents such as R1 as halogen; R2 hydrogen or methyl; R3, R4 hydrogen or methyl, and others specifying detailed substituent groups and combinations to produce compounds with specified properties.
Pharmaceutical composition comprising a compound of Formula (I)
Compositions that include a compound of Formula (I) or its salt together with a pharmaceutically acceptable carrier suitable for therapeutic administration.
Method of treating lysosomal storage disorders including Gaucher disease
Administering an effective amount of the compound of Formula (I) or salt thereof to a patient with a GBA gene mutation for treating the disease or preventing its symptoms, thereby providing a therapeutic benefit.
The claims cover the novel chemical compounds characterized by Formula (I), their specific substituent embodiments, pharmaceutical compositions containing these compounds, and therapeutic methods using these compounds to treat Gaucher disease and related disorders in patients with GBA gene mutations.
Stated Advantages
The compounds activate glucocerebrosidase enzyme activity without inhibiting it, unlike many prior chaperone molecules that act as inhibitors.
They are structurally distinct from iminosugars and may offer improved selectivity against other glycosidases.
They provide a novel chaperone therapy option addressing the unmet need for more effective Gaucher disease treatment that can reduce symptoms and increase active enzyme levels.
Documented Applications
Treatment of Gaucher disease in patients having a GBA gene mutation.
Prevention or reduction of severity of Gaucher disease symptoms in patients with GBA gene mutations.
Treatment and prophylactic use for Parkinson's disease in patients at risk or expressing symptoms with GBA gene mutation.
Treatment of dementia with Lewy bodies in patients who have a mutated GBA gene.
Methods for increasing the amount of beta glucocerebrosidase in white blood cells of patients with GBA gene mutations.
Pharmaceutical compositions comprising the compounds for therapeutic use in lysosomal storage disorders.
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