Treatment of inflammatory conditions and autoimmune diseases with glucose uptake inhibitors
Inventors
Kim, Ji-In • Olszewski, Kellen L. • Barsotti, Anthony M. • Poyurovsky, Masha V. • Liu, Kevin G. • Morris, Koi • Yu, Xuemei
Assignees
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Publication Number
US-11071735-B2
Publication Date
2021-07-27
Expiration Date
Abstract
This invention provides methods of treating inflammatory conditions and autoimmune diseases in a mammal, comprising administering to the mammalian subject in need thereof a therapeutically effective amount of a compound, or pro-drug thereof, or pharmaceutically acceptable salt or ester of said compound or pro-drug, wherein the compound is an inhibitor of glucose uptake. In particular aspects, the present invention provides a method of treating inflammatory conditions and autoimmune diseases in a mammal, and preferably a human, in which the glucose uptake inhibitor modulates the glucose transport of GLUT1 and GLUT3.
Core Innovation
The invention describes glucose uptake inhibitor compounds, including GLUT1 and GLUT3 modulators, for treating inflammatory conditions and autoimmune diseases. The therapeutic rationale is tied to immune cell aerobic glycolysis and the roles of GLUT1 and GLUT3 in activated T cells and innate immune cells.
The disclosure reports in vitro observations that dual GLUT1/GLUT3 inhibition suppresses glycolysis, cytokine secretion, and proliferation, and that GLUT1-selective inhibition is insufficient. The compounds are presented with a broad chemical scope, including compounds of Formula I and related structural formulas, together with preferred sub-variants and defined substituent variables.
The method is directed to treating an autoimmune disease or an inflammatory disease by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The structural framework in the provided examples is based on a quinazolinyl-phenoxy-pyrazole-anilide scaffold, with variable substitutions on the quinazoline ring and variable N-acyl side-chain groups.
Claims Coverage
The provided independent claims cover two themes: a structure-defined glucose uptake inhibitor compound and a method of treating autoimmune and inflammatory diseases by administering a therapeutically effective amount of Formula I compounds or salts. The inventive coverage is expressed through broad structural selection sets for multiple substituent and ring variables.
Structure-defined glucose uptake inhibitor compound
A compound having the structure or a pharmaceutically acceptable salt thereof, wherein R14c is C4–C6 alkyl optionally substituted with 1 to 3 substituents selected from halo and hydroxy; and R3c is selected from H and lower alkoxy, which may be unsubstituted or substituted by halo or lower alkoxy.
Treating autoimmune or inflammatory disease with a formula I compound
A method of treating an autoimmune disease or an inflammatory disease by administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, with R1, R12, R13, R14, X, and the additional formula variables constrained to the recited structural selection sets.
Overall claim coverage centers on structurally defined glucose uptake inhibitor compounds and therapeutic use of Formula I compounds for autoimmune and inflammatory disease treatment by administering a therapeutically effective amount.
Stated Advantages
Suppresses glycolysis.
Suppresses cytokine secretion.
Suppresses proliferation.
Dual GLUT1/GLUT3 inhibition is effective in contrast to GLUT1-selective inhibition being insufficient.
Documented Applications
Treatment of an autoimmune disease or an inflammatory disease by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
Treating inflammatory diseases, including mouse EAE and LPS/GalN cytokine models.
Treating inflammatory diseases selected from asthma, cardiovascular inflammation, renal inflammation, arteriosclerosis, or sepsis.
Treating fibrotic conditions selected from idiopathic pulmonary fibrosis, NASH, scleroderma, systemic sclerosis, or cirrhosis.
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