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-10925874-B2
Publication Date
2021-02-23
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
The invention provides substituted pyrazolopyrimidines and dihydropyrazolopyrimidines compounds, their manufacturing methods, pharmaceutical compositions containing these compounds, and methods of use in treating lysosomal storage disorders such as Gaucher disease. The compounds are of a defined general formula with specific substituent variations described in detail, which act as potent and selective activators of glucocerebrosidase (GCase). These compounds increase the amount and activity of GCase, particularly in lysosomes, and do not inhibit its enzymatic activity unlike previously known chaperones.
The problem being addressed is the need for novel molecular chaperone therapies for Gaucher disease, a genetic lysosomal storage disorder caused by mutations in the GBA gene leading to deficient glucocerebrosidase activity. Existing treatments like enzyme replacement and substrate reduction therapy are costly, and prior chaperone candidates such as isofagomine failed to reduce visceral symptoms despite increasing GCase levels in white blood cells. This invention addresses the unmet need for effective, selective small molecule chaperones that activate GCase and can be used therapeutically.
Claims Coverage
The patent claims include three independent claims covering pharmaceutical compositions and compounds, as well as methods of treating Gaucher disease and increasing beta glucocerebrosidase levels, with four main inventive features.
Pharmaceutical compositions comprising substituted pyrazolopyrimidines
A pharmaceutical composition comprising a substituted pyrazolopyrimidine compound of a defined formula, including pharmaceutically acceptable salts and carriers, optionally formulated as oral dosage forms.
Compounds as glucocerebrosidase activators
Specific substituted pyrazolopyrimidine compounds characterized by particular substituents (e.g., R5 and R7 both methyl, or other defined substituent patterns), including structurally distinct heterocyclic and aryl moieties, which act as potent activators of glucocerebrosidase.
Methods of treating Gaucher disease
Methods of treating or preventing symptoms of Gaucher disease in patients with GBA gene mutations by administering therapeutically effective amounts of the claimed compounds or pharmaceutical compositions to increase beta glucocerebrosidase levels and activity.
Methods of increasing beta glucocerebrosidase in white blood cells
Methods of increasing the amount of beta glucocerebrosidase enzyme in white blood cells by administering an effective amount of the claimed substituted pyrazolopyrimidine compounds or their pharmaceutical compositions to patients having GBA mutations.
The claims collectively cover novel substituted pyrazolopyrimidine compounds that selectively activate glucocerebrosidase, pharmaceutical compositions containing these compounds, and therapeutic methods to treat Gaucher disease by increasing enzyme levels and activity in relevant patient populations.
Stated Advantages
The compounds activate glucocerebrosidase without inhibiting enzyme activity, unlike most previously described chaperones which act as inhibitors.
The chemical class demonstrated is structurally distinct from iminosugars, allowing for potential selectivity against other glycosidases.
The compounds can increase beta glucocerebrosidase levels in lysosomes and white blood cells, facilitating therapeutic benefit in Gaucher disease patients.
Documented Applications
Treatment of lysosomal storage diseases, including Gaucher disease, particularly in patients with GBA gene mutations.
Prevention or reduction in severity of symptoms of Gaucher disease.
Increasing beta glucocerebrosidase enzyme levels and activity in white blood cells of patients with GBA mutations.
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