Benzathine analogs
Inventors
Chen, Beibei • Mallampalli, Rama K.
Assignees
University of Pittsburgh • US Department of Veterans Affairs
Publication Number
US-10159674-B2
Publication Date
2018-12-25
Expiration Date
2033-03-13
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Abstract
A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of:wherein X is a divalent linking moiety; andR1-R10 are each individually H, optionally-substituted alkyl, optionally-substituted alkoxy, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted heterocyclic, halogen, amino, or hydroxy, provided that at least one of R3 or R8 is an optionally-substituted alkyl, a substituted alkoxy, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted heterocyclic, or halogen.
Core Innovation
The invention pertains to a novel class of benzathine compounds, including their salts and esters, characterized by specific chemical structures defined by formulas involving a divalent linking moiety X and various substituents R1 through R10. These compounds act as inhibitors of the E3 ubiquitin ligase subunit FBXO3 by targeting a bacterial-like ApaG domain within FBXO3, which plays a role in ubiquitination and proteasomal degradation of the FBXO3-associated E3 ligase FBXL2.
The invention addresses the need for effective treatments for inflammatory diseases driven by cytokine storms, such as sepsis and pneumonia. Current therapies are insufficient due to their limited scope and efficacy. The invention introduces compounds that modulate inflammation by inhibiting FBXO3 activity, thereby reducing the degradation of FBXL2, decreasing TRAF protein levels, and ultimately suppressing excessive cytokine production.
These benzathine analog compounds demonstrate significant efficacy in both in vitro and in vivo models of inflammation and infection. They provide a targeted therapeutic approach to control cytokine storms, offering advantages over traditional anti-inflammatory drugs by specifically modulating the FBXO3 pathway, with potential benefits including reduced side effects and improved safety profiles.
Claims Coverage
The patent features two primary claims: one directed to compounds of formula II with specific structural features and substituents, and another to pharmaceutical compositions containing these compounds.
Compound structure with specified substituents
A compound, or pharmaceutically acceptable salt thereof, having a structure of formula II, characterized by a divalent linking moiety X and substituents R1-R10, where at least one of R3 or R8 is an optionally substituted alkyl, alkoxy, aryl, cycloalkyl, heterocyclyl, or halogen.
Specific N-heterocyclic substitutions at R3 and/or R8
At least one of R3 or R8 is an optionally substituted N-heterocycle selected from pyrrolyl, pyrrolidinyl, oxazolyl, pyrazolyl, tetrazolyl, and other heterocycles; in some claims, both R3 and R8 are such heterocycles.
Linker and substituents for enhanced activity
The divalent linking moiety X is cyclohexanediyl, with R3 and R8 as pyrrolidinyl groups, which enhances the compound's properties.
Pharmaceutical composition
A pharmaceutical formulation comprising at least one compound of formula II and at least one pharmaceutically acceptable excipient.
The patent claims target benzathine analog compounds with specific substitution patterns aimed at inhibiting FBXO3 via interaction with the ApaG domain. Focus is on compounds where R3 and R8 are N-heterocycles such as pyrrolidinyl linked through cyclohexanediyl, as well as compositions containing these entities, establishing a novel chemical approach to modulate inflammation.
Stated Advantages
The benzathine analog FBXO3 inhibitors exhibit potent anti-inflammatory effects by suppressing multiple cytokines involved in cytokine storms and related inflammatory conditions.
These compounds specifically target the bacterial-like ApaG domain in FBXO3, potentially offering high selectivity and minimizing off-target effects.
Inhibition of FBXO3 reduces TRAF protein levels and cytokine release, protecting tissues from injury in models of sepsis, pneumonia, and inflammation.
They provide a distinct therapeutic mechanism, potentially with fewer side effects compared to corticosteroids or NSAIDs.
Certain compounds also demonstrate antibacterial activity by targeting bacterial ApaG proteins, broadening their therapeutic scope.
Documented Applications
Treatment of inflammatory disorders characterized by cytokine storms, including sepsis, pneumonia, influenza, colitis, arthritis, Crohn’s disease, and systemic lupus erythematosus.
Inhibition of cytokine release mediated by TRAF proteins to prevent tissue damage during infections.
Use as antibacterial agents targeting pathogens like Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, H. influenza, and E. coli.
Therapeutic intervention in FBXO3-related conditions, such as malaria, lung toxicity, cancer, Alzheimer’s disease, and burn injuries.
Topical treatments for dermatological inflammatory diseases, including psoriasis and ear inflammation.
Formulations for systemic or local administration aimed at controlling inflammation and bacterial proliferation.
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