Benzathine analogs
Inventors
Chen, Beibei • Mallampalli, Rama K.
Assignees
University of Pittsburgh • US Department of Veterans Affairs
Publication Number
US-10369150-B2
Publication Date
2019-08-06
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 provides compounds, specifically benzathine compounds and their pharmaceutically acceptable salts or esters, that act as inhibitors of FBXO3, a component of an E3 ubiquitin ligase complex involved in regulating inflammation. These compounds have structures characterized by variable substituents and a divalent or tetravalent linking moiety, designed to interact with a bacterial-like ApaG domain within the FBXO3 protein, thereby inhibiting its activity.
The problem addressed by this invention stems from inflammatory disorders marked by a cytokine storm, leading to fatal immune reactions with excessive cytokine production such as TNFα, IL-1β, and IL-6. Existing treatments targeting single cytokines or receptors have proven ineffective, as systemic inflammation involves multiple inflammatory mediators. Furthermore, therapies like systemic corticosteroids have off-target effects and multi-drug resistance limits antimicrobial treatments. The invention aims to provide a novel therapeutic strategy by targeting FBXO3 to modulate the ubiquitination and degradation of FBXL2, an endogenous inhibitor of TRAF proteins which mediate cytokine release, thus mitigating the cytokine storm and tissue injury.
Claims Coverage
The patent includes one independent claim that defines compounds with a specific chemical structure targeting inflammatory pathways.
Compounds having a structure of formula VI
A compound, or a pharmaceutically acceptable salt thereof, having a defined structure comprising Ar1 and Ar2 independently selected from optionally substituted aryl or N-heterocyclic groups including pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl, wherein these groups may be substituted with alkyl, alkoxy, aminocarbonyl, halogen, or alkyl-substituted thiol substituents, exemplifying benzathine analogs that inhibit FBXO3 activity.
The single independent claim covers compounds with specific aryl and heterocyclic substituents designed to inhibit FBXO3 by interaction with its ApaG domain, forming the chemical basis for the anti-inflammatory therapeutics described.
Stated Advantages
The compounds are panreactive to numerous pro-inflammatory cytokines rather than targeting a single cytokine, potentially providing broader anti-inflammatory activity.
They target a unique bacterial-like ApaG domain in FBXO3, minimizing off-target effects and improving selectivity.
The inhibitors demonstrate the ability to reduce cytokine release, inflammation, and tissue damage in multiple animal models of diseases such as sepsis, pneumonia, and colitis.
They exhibit potent activity at doses below toxic levels, suggesting favorable therapeutic indices.
The compounds represent a novel mechanism distinct from corticosteroids and NSAIDs, possibly offering better toxicity profiles and reduced adverse effects.
Documented Applications
Treatment of inflammatory disorders characterized by cytokine storms, including sepsis, pneumonia, influenza-induced inflammation, edema, neuropathy, colitis, arthritis, Crohn’s disease, diabetes, skin, eye and ear inflammation, and systemic lupus erythematosis (SLE).
Use as antibacterial agents inhibiting bacterial growth of pathogens such as Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenza, or Escherichia coli.
Inhibition of pro-inflammatory cytokine release in subjects, particularly by reducing TRAF protein levels through targeting FBXO3.
Treatment of FBXO3-mediated disorders including malaria, toxic lung exposure, cancer, Alzheimer’s disease, and burn-related injuries.
Topical treatment for inflammatory conditions exemplified by TPA-induced ear edema.
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