Galactokinase inhibitors for the treatment and prevention of associated diseases and disorders
Inventors
Boxer, Matthew B. • Walsh, Martin J. • Liu, Li • Tanega, Cordelle D. • Shen, Min • Lai, Kent • Tang, Manshu • Auld, Douglas S.
Assignees
University of Utah Research Foundation Inc • US Department of Health and Human Services
Publication Number
US-9447087-B2
Publication Date
2016-09-20
Expiration Date
2031-09-23
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Abstract
Disclosed are inhibitors of human galactokinase of formula (1) that are useful in treating or preventing a galactokinase mediated disease or disorder, e.g., galactosemia. Also disclosed are a composition comprising a pharmaceutically acceptable carrier and at least one inhibitor of the invention, and a method of treating or preventing such disease or disorder in a mammal. Formula (I).
Core Innovation
The invention provides inhibitors of human galactokinase of formula (I), which are useful in treating or preventing galactokinase mediated diseases or disorders, such as galactosemia. The invention also provides pharmaceutical compositions comprising these inhibitors with pharmaceutically acceptable carriers, and methods of treatment or prevention in mammals by administering therapeutically or prophylactically effective amounts of these compounds.
Galactose is metabolized in the human body via the Leloir pathway, where galactokinase (GALK) catalyzes the conversion of alpha-D-galactose to galactose-1-phosphate (gal-1-p). Deficiency of the subsequent enzyme GALT causes classic galactosemia (CG), leading to accumulation of gal-1-p and severe neonatal disease and chronic complications even when dietary galactose is restricted. The invention addresses the unmet need for galactokinase inhibitors to prevent or treat galactokinase mediated diseases, aiming to reduce gal-1-p accumulation and related complications.
Furthermore, galactokinase modifies the PTEN/AKT pathway and is over-expressed in several tumors. Inhibition of GALK may down regulate PTEN/AKT signaling and thus potentially interfere with tumor growth or development. The invention provides compounds that inhibit galactokinase and methods for treating PTEN/AKT mis-regulated cancers in mammals, highlighting the dual therapeutic potential of these inhibitors in metabolic disorders and certain cancers.
Claims Coverage
The patent includes one independent claim encompassing a chemical compound and its various forms, along with related pharmaceutical compositions and therapeutic methods.
Compound of formula (I) as galactokinase inhibitors
A compound of formula (I) characterized by specific substituents R1, R2, R3, R4, R5, and parameters m, with detailed structural definitions including heteroaryl, alkyl, aryl and related moieties, optionally substituted, serving as inhibitors of human galactokinase.
Pharmaceutical composition comprising compound or salt
A pharmaceutical composition that comprises a pharmaceutically acceptable carrier and at least one compound described by formula (I) or its pharmaceutically acceptable salt.
Method for treating or preventing galactokinase mediated disease
A method to treat or prevent a human galactokinase mediated disease or disorder in a mammal by administering a therapeutically or prophylactically effective amount of a compound of formula (I), its salts, enantiomers, or diastereomers.
Method for treating PTEN/AKT mis-regulated cancer
A method of treating or preventing PTEN/AKT mis-regulated cancer in a mammal by administering a therapeutically or prophylactically effective amount of a compound according to formula (I) or its salt(s) or stereoisomers.
Method of reducing galactose-1-phosphate level in cells
A method to reduce galactose-1-phosphate levels in a cell by contacting the cell with an effective amount of a compound of formula (I), its salt, enantiomers, or diastereomers.
The claims define the core inventive features as a class of structurally defined galactokinase inhibitor compounds, their pharmaceutical formulations, and methods for treating galactokinase related diseases including classic galactosemia and certain cancers, as well as methods for reducing galactose-1-phosphate in cells.
Stated Advantages
The compounds provide inhibitors of galactokinase enzyme that can be used for prophylaxis and therapy of diseases preventable or treatable by inhibiting galactokinase.
Inhibition of GALK may down regulate the PTEN/AKT pathway, offering potential interference with tumor growth and development in various cancers.
Documented Applications
Treatment or prevention of classic galactosemia and other human galactokinase mediated diseases or disorders by administering effective amounts of the galactokinase inhibitors.
Treatment or prevention of PTEN/AKT mis-regulated cancers, including colon, head/neck, lung, ovary, pancreas, skin, breast, non-small cell lung, glioblastoma, prostate, and stomach cancers.
Reducing the level of galactose-1-phosphate in cells to alleviate or prevent disease progression associated with galactokinase activity.
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