Substituted fused pyrimidine compounds and uses thereof
Inventors
Krainc, Dimitri • Silverman, Richard B. • Zheng, Jianbin
Assignees
Publication Number
US-12291533-B2
Publication Date
2025-05-06
Expiration Date
2038-07-25
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Abstract
Disclosed are new small molecules having a substituted pyrimidine or substituted fused pyrimidine core structure and the uses thereof for modulating glucocerebrosidase activity. Also disclosed are pharmaceutical compositions comprising the small molecules which may be administered in methods of treating diseases or disorders associated with glucocerebrosidase activity, including Gaucher's disease and neurological diseases and disorders such as genetic and sporadic synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy associated with aberrant glucocerebrosidase activity. The small molecules may contain a fluorophore or may be conjugated to a fluorophore in order to prepare a fluorescent probe for use in high throughput screening methods to identify new modulators of glucocerebrosidase activity via fluorescence polarization.
Core Innovation
The invention discloses new small molecules featuring a substituted pyrimidine or substituted fused pyrimidine core structure that are used to modulate glucocerebrosidase activity. These small molecules can bind to glucocerebrosidase, optionally covalently, to increase or decrease the activity of the enzyme. The patent describes a range of possible substituents and structures, enabling the creation of diverse chemical entities with this core modular platform.
A key application of these molecules is in formulation as pharmaceutical compositions for treating diseases or disorders associated with aberrant glucocerebrosidase activity. The patent specifically mentions treating Gaucher's disease and neurological diseases and disorders such as genetic and sporadic synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Furthermore, these compounds can be conjugated to fluorophores, allowing their use as fluorescent probes in high throughput assays to discover additional modulators of glucocerebrosidase.
The invention addresses the problem that current treatments for diseases such as Gaucher's disease, especially enzyme replacement therapy, are expensive and ineffective for neuronopathic forms. Existing non-active site glucocerebrosidase modulators have suboptimal chemical and physical properties. The disclosed substituted pyrimidine and fused pyrimidine compounds improve on these by providing better polar surface area, solubility, increased rotatable bonds, and more hydrogen bonding functionalities, thereby offering improved candidates for modulating glucocerebrosidase activity.
Claims Coverage
There are two independent claims that define the main inventive features of this patent.
Substituted pyrimidine or fused pyrimidine compounds for modulating glucocerebrosidase
The core feature covers a compound or a salt or solvate thereof having a specific formula with: - A moiety (A) that is a saturated or unsaturated ring with 5 or 6 carbon atoms, possibly containing N, O, or S atoms, and optionally substituted at one or more ring positions with alkyl, alkoxy, halo, or haloalkyl. - Substituent X selected from hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, amino, aryl or heteroaryl optionally substituted at one or more positions with halo, haloalkyl, hydroxyl, amino, or pyrrolidinyl. - Substituent Y selected from hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, nitrogen-containing group, oxygen-containing group, aryl or heteroaryl optionally substituted at one or more positions with halo, haloalkyl, hydroxyl, amino, or pyrrolidinyl. - Substituent Z selected from hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, amino, aryl, or heteroaryl optionally substituted at one or more positions with halo, haloalkyl, hydroxyl, amino, or pyrrolidinyl. This structure is central to the patented chemical entities.
Pharmaceutical composition comprising the substituted pyrimidine or fused pyrimidine compound and a pharmaceutical carrier
A pharmaceutical composition comprising the compound, or a salt or solvate thereof, as defined by the inventive chemical feature and a pharmaceutical carrier. This extends the inventive scope from the compound itself to formulated pharmaceutical products.
In summary, the independent claims cover the novel substituted pyrimidine or fused pyrimidine compounds with defined substituents and their use in pharmaceutical compositions for modulating glucocerebrosidase activity.
Stated Advantages
The disclosed compounds possess improved chemical and physical properties compared to previously reported non-active site glucocerebrosidase modulators, including better polar surface area, solubility, increased number of rotatable bonds, and more potential hydrogen bonding members.
Some of the substituted pyrimidine and fused pyrimidine compounds are capable of highly activating glucocerebrosidase.
The disclosed compounds can be conjugated to fluorophores to create fluorescent probes for the study and high throughput screening of glucocerebrosidase modulators.
Documented Applications
Methods of treating diseases or disorders associated with glucocerebrosidase activity, including Gaucher's disease.
Treatment of neurological diseases and disorders such as genetic and sporadic synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy associated with aberrant glucocerebrosidase activity.
Use of the compounds as fluorescent probes in high throughput screening methods to identify new modulators of glucocerebrosidase activity via fluorescence polarization.
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