Substituted pyrazolopyrimidines as glucocerebrosidase activators
Inventors
Marugan, Juan Jose • Southall, Noel • Goldin, Ehud • Zheng, Wei • Patnaik, Samarjit • Sidransky, Ellen • Motabar, Omid • Westbroek, Wendy
Assignees
US Department of Health and Human Services
Publication Number
US-9974789-B2
Publication Date
2018-05-22
Expiration Date
2031-12-08
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Abstract
Substituted pyrazolopyrimidines and dihydropyrazolopyrimidines and related compounds, their methods of manufacture, compositions containing these compounds, and methods of use of these compounds in treating lysosomal storage disorders such as Gaucher disease are described herein. The compounds are of general Formula (I) in which variables R1-R7 and X are described in the application.
Core Innovation
Substituted pyrazolopyrimidines and dihydropyrazolopyrimidines and their related compounds are described, including their methods of manufacture, compositions containing these compounds, and methods of use. These compounds are represented by Formula (I) with various specific substituents defined, and include pharmaceutically acceptable salts. They serve as potent and selective activators of glucocerebrosidase (GCase), an enzyme involved in the breakdown of glucocerebroside within lysosomes.
The invention addresses Gaucher disease, a lysosomal storage disorder caused by inherited mutations in the GBA gene, leading to reduced GCase activity and accumulation of glucocerebroside, which causes cellular swelling and systemic symptoms. Existing treatments, such as enzyme replacement and substrate reduction therapy, are expensive and have limitations. The development of prior molecular chaperones like isofagomine showed increased GCase in white cells but failed to reduce symptoms, leaving an unmet need for novel chaperone therapies.
The disclosed substituted pyrazolopyrimidines provide an approach that activates rather than inhibits glucocerebrosidase, potentially improving folding and trafficking of the enzyme to lysosomes. The invention includes pharmaceutical compositions of these compounds and methods for treating Gaucher disease and increasing beta glucocerebrosidase activity in patients with GBA gene mutations, thus potentially preventing or reducing disease symptoms.
Claims Coverage
The patent includes multiple independent claims related to methods of increasing glucocerebrosidase activity and treating Gaucher disease using compounds of Formula (I). Three independent claims were identified focusing on methods of use.
Method of increasing beta glucocerebrosidase activity
A method of increasing beta glucocerebrosidase activity in cells by providing an effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt to a patient, where Formula (I) is defined with specified substituent groups (R1-R7 and X) as described in the patent.
Specific compound structures with defined substituents
The method where R6 is hydrogen and the compound falls within specific structural formulas with defined substituents R2 as hydrogen or methyl; R5 as C1-C4alkyl or difluoromethyl; and R7 as C1-C4alkyl, difluoromethyl, or phenyl, with further limitations on combinations of R5 and R7.
Method of treating or preventing Gaucher disease
A method of treating or preventing symptoms of Gaucher disease by administering an effective amount of a compound or pharmaceutically acceptable salt thereof, selected from a list of specific substituted pyrazolopyrimidine compounds disclosed in the patent.
The independent claims cover the use of substituted pyrazolopyrimidines and related compounds to increase beta glucocerebrosidase activity and treat Gaucher disease, defining specific structural features and compound examples that characterize the invention's therapeutic methods.
Stated Advantages
The compounds activate glucocerebrosidase rather than inhibit it, unlike most known chaperones, improving enzyme folding and trafficking.
They represent a novel chemical class distinct from iminosugars, potentially offering increased selectivity against other glycosidases.
The compounds may provide effective therapeutic benefits for Gaucher disease patients with improved outcomes over existing treatments.
Documented Applications
Treating lysosomal storage disorders, including Gaucher disease, in patients with GBA gene mutations.
Preventing or reducing the severity of symptoms of Gaucher disease in patients having a GBA gene mutation.
Increasing the amount of beta glucocerebrosidase in white blood cells or lysosomes in patients with Gaucher disease or GBA gene mutations.
Veterinary applications to treat lysosomal storage disorders in non-human mammals such as horses, livestock, and companion animals.
Diagnostic or research use involving in vitro applications with body fluids and cells from various mammals.
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