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-9353117-B2
Publication Date
2016-05-31
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 relates to substituted pyrazolopyrimidines and dihydropyrazolopyrimidines and related compounds, their methods of manufacture, compositions containing these compounds, and their use in treating lysosomal storage disorders such as Gaucher disease. The compounds are characterized by Formula (I), where the variables R1-R7 and X are defined with specific substituents and ring systems detailed in the application.
The problem addressed relates to Gaucher disease, a rare genetic disorder caused by mutations in the GBA gene that reduce the activity of glucocerebrosidase (GCase), an enzyme responsible for breaking down glucocerebroside in lysosomes. Current treatments include enzyme replacement and substrate reduction therapies, which are costly and have limitations, such as the halted development of the iminosugar isofagomine due to insufficient clinical efficacy. There is an unmet need for novel chaperone therapies that effectively increase GCase activity and reduce Gaucher disease symptoms.
The invention provides a chemical class of pyrazolopyrimidines and dihydropyrazolopyrimidines that act as potent and selective activators of glucocerebrosidase rather than inhibitors. These compounds function as molecular chaperones that assist the proper folding and lysosomal trafficking of mutant GCase enzyme. The compounds' structural distinctiveness from iminosugar chaperones and their activation of GCase make them promising candidates for treating Gaucher disease and preventing its symptoms in patients with GBA mutations.
Claims Coverage
The patent contains several independent claims primarily directed to compounds of Formula (I), pharmaceutical compositions, and methods of treatment using these compounds. The following inventive features summarize the key aspects claimed independently.
Compound of Formula (I) with defined substituents
The invention claims compounds of Formula (I) characterized by specific substitutions at positions R1 to R7 and associated ring systems. These substituents include various alkyl, alkenyl, alkynyl, carbocyclic, and heterocyclic groups with further optional substituents specified in detail, defining structurally distinct pyrazolopyrimidines and dihydropyrazolopyrimidines.
Pharmaceutical compositions containing the compounds
Pharmaceutical compositions comprising a compound of Formula (I) or its pharmaceutically acceptable salts together with a pharmaceutically acceptable carrier are claimed. The compositions can be formulated into various dosage forms including oral dosage forms.
Method of treating Gaucher disease using the compounds
Methods for treating Gaucher disease or preventing its symptoms in patients with GBA gene mutation by administering an effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt. The method includes increasing the amount of beta-glucocerebrosidase in the patient's white blood cells through such administration.
The independent claims cover the novel substituted pyrazolopyrimidine and dihydropyrazolopyrimidine compounds, their pharmaceutical compositions, and their use in methods for treating Gaucher disease by enhancing glucocerebrosidase activity. These claims define the structural features, formulations, and therapeutic applications of the compounds.
Stated Advantages
The compounds do not inhibit but activate glucocerebrosidase, potentially improving enzyme activity within the lysosome.
Their chemical class is structurally distinct from iminosugars, promising better selectivity against other glycosidases.
The compounds function as potent and selective chaperones of glucocerebrosidase, addressing a need for novel effective therapies for Gaucher disease.
Documented Applications
Treatment of lysosomal storage disorders, including Gaucher disease, in patients having GBA gene mutations.
Prevention or reduction of the severity of symptoms of Gaucher disease in patients with GBA gene mutations.
Increasing the amount of beta-glucocerebrosidase enzyme in the white blood cells of patients with GBA gene mutations.
Veterinary applications for treatment of Gaucher disease in mammals such as horses, livestock, and pets.
Diagnostic and research applications involving various mammals, including rodents, rabbits, primates, and swine, and their biological samples.
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