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-10471061-B2
Publication Date
2019-11-12
Expiration Date
2031-09-23
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Abstract
Disclosed are inhibitors of human galactokinase of formula (I) 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 (GALK) of formula (I) useful in treating or preventing galactokinase-mediated diseases or disorders, such as galactosemia. It also relates to pharmaceutical compositions comprising these inhibitors and methods of administering them to mammals to treat or prevent such diseases. These compounds modulate the enzymatic activity of GALK, reducing levels of galactose-1-phosphate in cells.
The background highlights the metabolic role of galactokinase in the Leloir pathway, converting α-D-galactose to galactose-1-phosphate, which is further metabolized by galactose-1-phosphate uridyltransferase (GALT). Deficiency in GALT causes classic galactosemia (CG), a potentially lethal disorder characterized by accumulation of galactose-1-phosphate leading to severe neonatal disease and long-term complications in patients. Dietary restriction of galactose is insufficient since endogenous galactose production occurs. Further, evidence links galactose-1-phosphate accumulation to chronic complications in CG, and suggests that GALK inhibitors could alleviate these issues by lowering galactose-1-phosphate levels.
Additionally, GALK1 regulation impacts the PTEN/AKT pathway, which is involved in tumor growth; GALK1 is overexpressed in various tumors. Therefore, inhibiting GALK could also interfere with PTEN/AKT mis-regulated cancers, representing a novel therapeutic avenue. The invention addresses the unmet need for GALK inhibitors useful for prophylaxis and therapy of diseases associated with GALK activity.
Claims Coverage
The patent discloses one independent method claim focused on treating galactosemia by administering specific galactokinase inhibitor compounds or their salts.
Method of treating galactosemia with galactokinase inhibitors
Administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient having galactosemia to inhibit the enzymatic activity of galactokinase.
Structural specificity of galactokinase inhibitors
Compounds wherein R5 is selected from specified heteroaryl substituents including benzoxazol-2-yl and its derivatives, benzoimidazol-2-yl, benzothiazol-2-yl, indolyl, furanyl, thiopheneyl, imidazolyl, thiazolyl, pyrazolyl, and pyridinyl groups, optionally further substituted as described.
Substitution patterns of R2, R3, and R4 groups
Compounds wherein R2 is phenyl or heteroaryl optionally substituted with halogen, trifluoromethyl, alkyl, alkoxy, aryloxy, and dialkylamino groups; R3 is selected from —NH-alkyl, —NH-cycloalkyl, —NH-aryl, —NH-alkylaryl, —NH-heteroaryl, and —NR12R13 with defined substitution options; R4 is hydrogen or alkyl; or R3 and R4 together form a specified bicyclic group.
Method of administering specific compound subsets
Treatment methods wherein the compound used is selected from disclosed specific compound examples representing various embodiments of the formula (I) and its sub-formulas (Ia) and (Ic).
Pharmaceutical formulation and patient selection
Compounds are delivered with a pharmaceutically acceptable carrier, and patients treated may be deficient in galactose-1-phosphate uridyltransferase (GALT).
The independent claims cover methods of treating galactosemia by administering galactokinase inhibitors of defined chemical structures, including specific substitutions and embodiments, with pharmaceutical carriers, targeting patients with galactosemia including those with GALT deficiency.
Stated Advantages
The invention provides effective inhibitors of galactokinase useful for the treatment and prevention of classic galactosemia and related disorders.
The compounds selectively inhibit galactokinase without cytotoxicity and without redox cycling effects, indicating genuine target activity and improved safety.
Inhibition of GALK may interfere with PTEN/AKT mis-regulated cancers, offering potential therapeutic benefit in multiple tumor types.
Documented Applications
Treatment and prevention of galactosemia in patients, including those with galactose-1-phosphate uridyltransferase (GALT) deficiency.
Reduction of galactose-1-phosphate levels in cells by contacting with the inhibitor compounds.
Treatment or prevention of PTEN/AKT mis-regulated cancers such as colon, head/neck, lung, ovary, pancreas, skin, breast, glioblastoma, prostate, and stomach cancers using the galactokinase inhibitors.
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