Compositions and therapeutic methods
Inventors
Acharya, Suchismita • Panda, Santosh K • Das, Pragnya • Agarwal, Beamon
Assignees
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Publication Number
US-11207343-B2
Publication Date
2021-12-28
Expiration Date
Abstract
The present invention is directed to novel products, variants, pharmaceutically acceptable salts and prodrugs thereof, and medical use of such compounds for the treatment and/or management of sepsis, septicemia, septic shock, ocular infection, ocular inflammation, ocular angiogenesis, rheumatoid arthritis (RA), atherosclerosis, inflammatory bowel diseases (IBD), asthma, chronic obstructive pulmonary disease, fever syndromes, cachexia, psoriasis, autoimmune diseases, cardiac diseases, retinoblastoma, cancer and/or any disorder associated with inflammation, immunomodulation and microbial infection.
Core Innovation
The document describes small, water-soluble chitooligosaccharide-based compounds, including chitohexaose, chitoheptaose, chitooctaose, and derivatives, as TLR4 antagonists. The compounds are presented as pharmaceutical compositions comprising a compound according to Formula (I) or a pharmaceutically acceptable salt, with defined substituent groups and beta anomer stereochemistry at a pH of 6.5-7.4.
The document addresses inflammatory and infectious disease states associated with TLR4-mediated inflammation. It reports inhibition of inflammatory biomarkers induced by LPS and HMGB1-driven inflammatory responses, with reduced TNF-α, IL-1β, and IL-6, and upregulation of anti-inflammatory IL-10 and M2-associated markers.
The document further reports therapeutic activity in in vitro and in vivo inflammatory models, including protection in lethal E. coli endotoxemia and CLP polymicrobial sepsis models. For ocular inflammation and ocular angiogenesis, it reports HMGB1-driven downregulation of VEGF and reduced CNV lesion size in a laser-induced wet AMD mouse model. The compounds are also described as having broad-spectrum antimicrobial activity against gram-positive and gram-negative bacteria and Candida, together with proposed cell membrane disruption, lack of plasma protein binding, and non-toxic fibroblast activity.
Claims Coverage
The provided claims define three independent claim families covering a Formula (I) pharmaceutical composition with specified structural features and pH conditions, a pharmaceutical composition comprising one or more selected compounds, and a Formula (I) pharmaceutical composition formulated at pH 6.5-7.4. The inventive features center on defined Formula (I) structures with beta anomeric stereochemistry and pH range, plus a separate composition including selected compounds.
Formula (I) pharmaceutical composition with defined substituents and beta anomer at pH 6.5-7.4
A pharmaceutical composition comprising a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, where R and R1 define the substituent classes, R2 is H, C(O)R1, or an aceloxy alkyl carbamate structure, X-O is linked to the anomeric carbon via beta anomer stereochemistry at a pH of 6.5-7.4, and R5 includes piperidine nitroxyl or related nitroxyl/n-hydroxylamine groups, with n=0-7.
Selected compound pharmaceutical composition
A pharmaceutical composition comprising one or more compounds or a pharmaceutically acceptable salt thereof selected from a set of selected compounds.
Formula (I) pharmaceutical composition formulated at pH 6.5-7.4
A pharmaceutical composition comprising a compound according to Formula (I), or a pharmaceutically acceptable salt thereof, at a pH of 6.5-7.4, where R and R1 define the substituent classes, R2 is H or C(O)R1 or an aceloxy alkyl carbamate of the defined structure, R3 is selected from H, CH3, C2H5, R4 is a substituted alkyl group, X-O is linked to the anomeric carbon via beta anomer stereochemistry, and R5 includes heterocycloalkyl, piperidine nitroxyl, or piperidine N-hydroxylamine.
Overall, the claims define pharmaceutical compositions centered on Formula (I) chitooligosaccharide-based compounds with specified substituent options and beta anomeric stereochemistry, explicitly tied to formulation at pH 6.5-7.4, plus a separate composition that includes one or more selected compounds.
Stated Advantages
Inhibition of LPS- and HMGB1-induced inflammatory biomarkers, including TNF-α, IL-1β, and IL-6.
Upregulation of anti-inflammatory IL-10 and M2-associated markers.
Protection in lethal E. coli endotoxemia and CLP polymicrobial sepsis models.
Downregulation of HMGB1-driven VEGF and reduced CNV lesion size in a laser-induced wet AMD mouse model.
Broad-spectrum antimicrobial activity against gram-positive and gram-negative bacteria and Candida, including biofilm inhibition/eradication.
Proposed disruption of cell membrane, lack of plasma protein binding, and lack of fibroblast toxicity.
Documented Applications
Inflammatory and infectious indications including sepsis/septic shock and SIRS.
Ocular inflammation and ocular angiogenesis, including AMD/CNV and laser-induced wet AMD models.
Other inflammation-linked disorders including rheumatoid arthritis, atherosclerosis, inflammatory bowel diseases, asthma, COPD, psoriasis, autoimmune diseases, and cardiac diseases.
Microbial infection, including gram-positive and gram-negative bacteria, methicillin susceptible/resistant S. aureus, and Candida, with activity against biofilm formation/eradication.
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