Human GLUT5 specific inhibitors and methods of treatment
Inventors
Oprea, Tudor I. • Bologa, Cristian George • Ursu, Oleg • Choe, Jun-Yong • Iancu, Cristina
Assignees
Rosalind Franklin University of Medicine and Science • UNM Rainforest Innovations
Publication Number
US-10822325-B2
Publication Date
2020-11-03
Expiration Date
2036-06-10
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Abstract
The present invention relates to compounds which have been discovered to be potent ligands (inhibitors) of human GLUT5 (glucose transporter type 5), a facilitative glucose transporter that transports fructose, and their use as ligands assays which can uncover additional ligands of GLUT5, having the potential for being used as drugs. In addition, the present invention is directed to compounds, chemical compositions and methods for treating disease states and conditions which are mediated through GLUT5, including such disease states and conditions as GLUT5 deficiency syndrome, diabetes (type I and II), cancer, metabolic diseases including metabolic syndrome and fatty liver disease, among others.
Core Innovation
The present invention pertains to compounds that act as potent ligands or inhibitors of human GLUT5, a fructose-specific facilitative glucose transporter encoded by the SLC2A5 gene. The invention includes specific compounds, such as N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine (MSNBA), that bind to and inhibit GLUT5, as well as additional chemical compositions, pharmaceutical formulations, and food compositions containing such inhibitors. The core concept extends to methods for modulating GLUT5 activity by administering these compounds, thereby impacting fructose transport and absorption.
The invention addresses the critical problem that excessive fructose consumption and GLUT5-related pathologies, including diabetes, cancer, metabolic syndrome, and fatty liver disease, lack effective and selective therapeutic interventions. Previously available inhibitors affect other GLUT family members responsible for glucose transport, leading to undesirable side effects such as disruption of glucose homeostasis. No selective GLUT5-specific inhibitors had been described prior to this invention.
In response, the inventors discovered a collection of fourteen compounds, particularly MSNBA, which selectively inhibit GLUT5 activity without affecting glucose transporters like GLUT1-4 or bacterial GlcPSe. These ligands serve as chemical probes for GLUT5, providing a means to not only inhibit fructose absorption for therapeutic purposes but also to identify other GLUT5 modulators via binding assays. The invention further proposes the use of such inhibitors in treating a range of GLUT5-mediated disease states by incorporating them in pharmaceuticals or as additives to fructose-containing foods to reduce intestinal fructose uptake.
Claims Coverage
There are two independent claims establishing the main inventive features of the patent.
Method for therapeutically treating GLUT5-mediated diseases
A method of therapeutically treating a disease state or condition which is mediated through GLUT5 in a patient in need comprises administering a therapeutically effective amount of a composition containing at least one compound according to a specified chemical structure. This structure encompasses compounds identified as potent ligands or inhibitors of human GLUT5, including but not limited to MSNBA and pharmaceutically acceptable salts thereof. The method can also include administering an additional bioactive agent chosen from agents for diabetes (type I or II), metabolic syndrome, cardiovascular agents, or statins, either individually or in mixtures, to address comorbidities as disclosed in the claims.
Method for treating GLUT5-mediated diseases with defined compound
A method of therapeutically treating a disease state or condition which is mediated through GLUT5 in a patient in need, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound according to the chemical structure specified (as shown in the claim and figures of the patent). The diseases specifically mentioned by the claims include diabetes type I and II, metabolic diseases, metabolic syndrome, fatty liver disease, and non-alcoholic fatty liver disease. The covered compound includes MSNBA or its pharmaceutically acceptable salt forms.
In summary, the patent covers methods of treating GLUT5-mediated diseases by administering GLUT5-specific inhibitory compounds, particularly MSNBA and related structures, optionally in combination with additional therapeutic agents, to specifically address conditions such as diabetes, metabolic syndrome, and fatty liver disease.
Stated Advantages
The inhibitors are specific for GLUT5 and do not affect glucose transport by other GLUT family members, thereby minimizing unwanted side effects on glucose metabolism.
The invention provides new chemical probes and standards for identifying additional GLUT5 modulators through displacement assays, aiding in drug discovery and development.
GLUT5 inhibitors can be used to reduce the absorption of fructose from food, offering a therapeutic approach for diseases where fructose metabolism is implicated.
Documented Applications
Treatment of disease states and conditions mediated through GLUT5, including GLUT5 deficiency syndrome, diabetes (type I and II), cancer, metabolic diseases, metabolic syndrome, and fatty liver disease (including non-alcoholic fatty liver disease).
Use in assays as ligands for identifying and evaluating the activity of compounds as potential GLUT5 modulators.
Incorporation in food compositions comprising fructose to reduce absorption of fructose from the intestines in a patient or subject.
Reduction of fructose absorption by adding a GLUT5 inhibitor to a food composition or ingesting the inhibitor with fructose-containing foods.
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