Benzathine analogs
Inventors
Chen, Beibei • Mallampalli, Rama K.
Assignees
University of Pittsburgh • US Department of Veterans Affairs
Publication Number
US-10869866-B2
Publication Date
2020-12-22
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 relates to compounds and methods for inhibiting pro-inflammatory cytokine release by targeting the F-box E3 ubiquitin ligase subunit FBXO3. Specifically, the invention discloses benzathine compounds, among other FBXO3 inhibitors, that selectively inhibit FBXO3 activity by interacting with its bacterial-like ApaG domain, thereby preventing FBXO3-induced ubiquitination and degradation of FBXL2. FBXL2 itself targets TRAF proteins for polyubiquitination and degradation, which are critical adapters mediating cytokine gene expression. Thus, FBXO3 inhibition stabilizes FBXL2, leading to decreased TRAF levels and reduced cytokine release from immune and epithelial cells.
The problem solved by this invention addresses the limitation of existing treatments for inflammatory disorders, such as sepsis and pneumonia, which often fail due to targeting single receptors or cytokines and associated toxicities. The invention recognizes that inflammatory disorders are mediated by multiple pro-inflammatory cytokines released via complex signaling pathways, including TRAF-mediated pathways. Existing therapeutics like corticosteroids or single-target antibodies have shown poor mortality outcomes and broad systemic effects. There is a need for novel therapeutics that modulate a broader range of inflammatory mediators with improved specificity and safety profiles.
The invention further uncovers a novel molecular pathway wherein FBXO3 promotes inflammation by ubiquitinating FBXL2, leading to stabilization of TRAF proteins and exaggerated cytokine storms that contribute to tissue injury and organ failure. The invention includes the characterization of naturally occurring loss-of-function mutations in FBXO3 that reduce cytokine release and inflammatory injury, validating FBXO3 as a promising therapeutic target. Small molecule inhibitors of FBXO3, such as benzathine analogs exemplified by BC-1215, are disclosed, which bind the FBXO3 ApaG domain, inhibit FBXO3-mediated ubiquitination of FBXL2, reduce TRAF protein levels, decrease the release of a broad panel of pro-inflammatory cytokines, and ameliorate inflammatory injury in diverse in vivo models.
Claims Coverage
The patent contains one independent claim covering a compound having a specified structure of formula II, including pharmaceutically acceptable salts and esters thereof. The claim focuses on benzathine analogs defined by their substituents and linking moieties.
Compound structure of formula II with specified substituents
The claimed compounds have a structure of formula II featuring a divalent linking moiety X, and substituents R1 through R10 which are individually H or optionally substituted alkyl, alkoxy, aryl, cycloalkyl, heterocyclic, halogen, amino, or hydroxy, with at least one of R3 or R8 being optionally substituted alkyl, substituted alkoxy, aryl, cycloalkyl, heterocyclic, or halogen.
Inclusion of N-heterocyclic substituents at R3 and R8
Certain embodiments specify that R3 and R8 are N-heterocyclic groups chosen from imidazolyl, pyridyl, pyrazolyl, oxadiazolyl, or pyrimidinyl, and in preferred cases are pyrazolidinyl.
Pharmaceutical compositions containing the compounds
Pharmaceutical compositions comprising at least one compound of formula II and at least one pharmaceutically acceptable additive are claimed.
Specific linking moiety and substituent configurations
Claims specify embodiments where X is phenylenediyl and R3 and R8 are each pyrazolidinyl or other N-heterocycles, with remaining substituents R1, R2, R4, R5, R6, R7, R9, and R10 being hydrogen.
The claim covers benzathine analog compounds characterized by defined structures featuring substituents that confer FBXO3 inhibitory activity. Key inventive features include the presence of specific N-heterocyclic substituents at critical positions, a defined linking moiety, and inclusion in pharmaceutical compositions. The claims focus on molecular structure and substituent patterns critical for interaction with the FBXO3 ApaG domain to inhibit inflammatory cytokine release.
Stated Advantages
The compounds selectively inhibit FBXO3, preventing FBXL2 degradation and reducing levels of multiple pro-inflammatory cytokines, resulting in potent anti-inflammatory effects.
They exert pan-reactive inhibition across a broad spectrum of cytokines rather than targeting a single cytokine, potentially offering broader efficacy in inflammatory disorders.
The molecular target FBXO3 contains a bacterial-like ApaG domain absent in other mammalian proteins, offering potential for greater drug selectivity and reduced off-target effects.
The FBXO3 inhibitors demonstrated efficacy in multiple in vivo models of inflammation and infection, including sepsis, pneumonia, influenza-induced lung injury, ear and paw edema, colitis, and cancer.
The compounds inhibit bacterial growth on surfaces, suggesting potential antibacterial utility as well.
Documented Applications
Treatment and prophylaxis of inflammatory disorders characterized by cytokine storm or hypercytokinemia, including sepsis, pneumonia, influenza-induced inflammation, edema, colitis, arthritis, Crohn's disease, diabetes, skin, eye and ear inflammation, systemic lupus erythematosis, and autoimmune diseases.
Inhibition of pro-inflammatory cytokine release in subjects at risk of or suffering from inflammatory diseases.
Use as antibacterial agents inhibiting bacterial growth in subjects or on surfaces by interacting with bacterial ApaG protein.
Treatment of FBXO3-mediated disorders such as malaria, toxic lung exposure, cancer, Alzheimer's disease, and burn-related injury.
Use in pharmaceutical compositions for administration via various routes including oral, parenteral, topical, and pulmonary delivery.
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