Benzathine analogs
Inventors
Chen, Beibei • Mallampalli, Rama K.
Assignees
University of Pittsburgh • US Department of Veterans Affairs
Publication Number
US-9359284-B2
Publication Date
2016-06-07
Expiration Date
2033-03-13
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 relates to compounds, particularly benzathine analogs, that inhibit the activity of the F-box protein FBXO3, which is implicated in the regulation of inflammation through modulation of pro-inflammatory cytokine release. FBXO3 acts as an E3 ubiquitin ligase subunit that targets another E3 ligase subunit, FBXL2, for ubiquitination and proteasomal degradation. FBXL2 normally suppresses inflammatory responses by targeting TRAF family proteins for degradation, which mediate cytokine secretion from inflammatory cells.
The disclosed compounds, including benzathine analogs and related structures, are designed to selectively inhibit FBXO3, thereby preventing degradation of FBXL2, reducing TRAF protein levels, and subsequently suppressing the cytokine storm associated with inflammatory disorders such as sepsis and pneumonia. The compounds act by interacting with a unique bacterial-like ApaG domain within FBXO3, not found in mammalian proteins, conferring selective inhibition.
The problem addressed is the failure of prior therapies that target single pro-inflammatory cytokines or receptors, which are insufficient due to the complex and multifaceted nature of systemic inflammation and sepsis. Existing treatments, such as corticosteroids or targeted cytokine blockers, have not improved mortality. Therefore, there is a need for small molecule anti-inflammatory therapeutics with novel targets capable of broadly modulating the inflammatory cascade by targeting upstream regulators like FBXO3.
Claims Coverage
The patent contains two independent claims, presenting distinctive structural compound definitions.
Compounds having a structure of formula II with specific substituents
The invention claims compounds, or pharmaceutically acceptable salts or esters thereof, having a structure of formula II where X is a divalent linking moiety, and substituents R1 to R10 are independently selected from hydrogen, optionally-substituted alkyl, alkoxy, aryl, cycloalkyl, heterocyclic, halogen, amino, or hydroxy, with the requirement that at least one of R3 or R8 is an optionally-substituted alkyl, substituted alkoxy, aryl, cycloalkyl, heterocyclic, or halogen.
Compounds having a specified alternative structure
The invention claims compounds, or pharmaceutically acceptable salts or esters thereof, having the disclosed alternative molecular structure set forth without substitutions detailed here, covering structural variations complementary to those in formula II.
The claims cover novel compounds specifically characterized by defined molecular frameworks and substituent patterns that confer FBXO3 inhibitory activity, underpinning their use as selective anti-inflammatory agents.
Stated Advantages
The compounds provide potent anti-inflammatory activity by broadly inhibiting multiple pro-inflammatory cytokines mediated through FBXO3 inhibition.
They target a unique bacterial-like molecular signature within FBXO3, enhancing drug selectivity and potentially reducing off-target effects.
The compounds demonstrate efficacy in preventing cytokine storms and tissue damage in various animal models of inflammation, including sepsis and pneumonia.
They offer improved toxicity profiles compared to glucocorticoids and nonsteroidal anti-inflammatory drugs by acting through a novel E3 ligase mechanism.
Documented Applications
Treatment of inflammatory disorders mediated by cytokine release, particularly cytokine storm conditions such as sepsis and pneumonia.
Inhibition of pro-inflammatory cytokine release in subjects experiencing immune activation.
Treatment of various acute and chronic inflammatory disorders including asthma, pulmonary fibrosis, colitis, arthritis, systemic lupus erythematosis, and viral-induced inflammation.
Use as antibacterial agents to inhibit bacterial growth in subjects or on surfaces, via interaction with the bacterial ApaG protein.
Treatment of FBXO3-mediated conditions such as malaria, toxic lung exposure, cancer, Alzheimer's disease, or burn-related injury.
Interested in licensing this patent?