Anti-infective and anti-inflammatory compounds
Inventors
Pietrzik, Nikolas • Burnet, Michael W. • Baeuerlein, Christiane • Eggers, Mary • Guse, Jan-Hinrich • Hahn, Ulrike • Strass, Simon
Assignees
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Publication Number
US-11420995-B2
Publication Date
2022-08-23
Expiration Date
Abstract
Lysosomally accumulated substances that release a nitroxy group, or a short chain fatty acid or a product of anaerobic metabolism or a thiol or a sulfide often from an ester or similar labile linkage have anti-inflammatory, anti-cancer and anti-bacterial activity. They are useful in treating infectious, inflammatory and malignant disease.
Core Innovation
The invention relates to a compound, or salt thereof, comprising an Amphiphilic Lysosomally trapped Compound (ALC) defined as Formula 6. The Formula 6 scaffold includes a macrolide ring or macrolide ring system with variable substituents, including R1, R2, R3, Mac, R3′, and further group-connection options, together with heterocyclic moiety options such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, 1-substituted piperazine, or morpholine.
The structure is constrained to include at least one moiety consisting of -ONO2 or -NNO2, with optional nitro and related groups and defined substituent patterns such as -NO(y) where y is 2, C(=O)OR7′, C(=O)R7′, and connectivity via W′ groups or via connectivity between R4′ and R5′ bearing atoms through C(=O)- or W′. The scaffold further includes additional defined groups and linking options, including carbonyl-containing alternatives and C(O) or W connectivity.
The invention also frames the ALC as lysosomally trapped amphiphilic chemistry that, after contacting immune and/or epithelial cells, causes intracellular release of products of Anaerobic Metabolism (PAM). The intracellularly released PAM products include Toll-like-receptor (TLR) ligands, short chain fatty acids, nitric oxide, H2S and sulfides, polyamines, decarboxylated amino acids, and phenylpropionic acid, resulting in an anti-infective barrier or anti-infective response.
Claims Coverage
The claim coverage centers on one independent claim defining a broad Amphiphilic Lysosomally trapped Compound (ALC) of Formula 6, with multiple variable substituent options, a macrolide ring or macrolide ring system, and nitro-related moieties. The inventive features are primarily structural, with a further use-related feature tied to intracellular release of PAM products after contacting immune or epithelial cells.
Amphiphilic lysosomally trapped compound of Formula 6
A compound, or salt thereof, comprising an Amphiphilic Lysosomally trapped Compound (ALC) defined as Formula 6 with variable substituents R1, R2, R3, and Mac, optional nitro and XNO(y) functionality, and at least one moiety consisting of -ONO2 or -NNO2.
Macrolide ring or macrolide ring system
The compound includes a macrolide ring or macrolide ring system with defined internal structural motifs and substituent options, including carbonyl-containing alternatives and C(O) or W connectivity.
Heterocyclic moiety options
The compound permits N(R1R2) to be an aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, 1-substituted piperazine, or morpholine moiety.
Contacting immune and epithelial cells to produce intracellular PAM release
A method of contacting immune cells and/or epithelial cells with a compound, or salt thereof, comprising an ALC to cause intracellular release of products of Anaerobic Metabolism (PAM) and form an anti-infective barrier or response.
The claim coverage is anchored by a broadly defined ALC scaffold of Formula 6 that includes a macrolide ring system, nitro-related moieties, and multiple selectable heterocyclic options. The provided material also ties the compound to intracellular PAM release and an anti-infective barrier or anti-infective response.
Stated Advantages
Improved anti-microbial activity via enhanced phagocytosed bacterial killing.
Supports anti-inflammatory and anti-cancer effects.
Reduces systemic exposure compared to extracellular NO/SCFA donors.
Induces formation of an anti-infective barrier or an anti-infective response in immune and/or epithelial cells.
Documented Applications
Stimulating immune or epithelial cells to form an anti-infective barrier or anti-infective response by contacting the cells with the compound and causing intracellular release of PAM products.
Treating infections and/or inflammation through intracellular release of anaerobic metabolism products, including PAM products such as SCFAs and nitric-oxide-related species.
Testing in in vivo inflammation/infection model contexts including DSS colitis and EAE, and use of TNFβ1 and phagocytosis killing assays.
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