Compounds and therapeutics uses thereof
Inventors
WESTBY, Michael • GLOSSOP, Melanie • WATSON, Christine
Assignees
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Publication Number
US-11406683-B2
Publication Date
2022-08-09
Expiration Date
Abstract
The invention relates to novel compounds with the ability to link an immune response to a pathogen, to the use of said compounds in a disease or disorder mediated and/or caused by an infective agent, to compositions containing said compounds, processes for their preparation and to novel intermediates used in said process.
Core Innovation
The invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, in which L represents a binding moiety which is a cationic anti-microbial peptide linked to X1 by an amine and F represents rhamnose. The structure includes S1 and S2 as bonds or spacers selected from specified aliphatic and optionally substituted chain structures, together with Y1 and Y2 for defining the X1-related connectivity.
X1 is defined as a bond or C(O)-Y1, and Y1 and Y2 are independently bonds or selected functional groups chosen from O, S, NH, C(O), NHC(O), or C(O)NH. Cy is defined as biphenyl, with the Y1-S1-X1 group present on either phenyl ring and the [F-S2-Y2]m group or groups present on either phenyl ring, thereby specifying the linkage architecture between rhamnose and the cationic anti-microbial peptide binding moiety.
The disclosure characterizes the compounds by LCMS/MS mass spectrometry for Examples 4–6 and reference examples 7–11, and describes illustrated chemical structures. The interaction theme of F (rhamnose) and anti-rhamnose IgG is used to assess IgG recruitment and complement deposition on bacterial surfaces, including flow cytometric readouts for Pseudomonas aeruginosa PA01 and E. coli K1:O18ac:H7 in the presence of the Example compounds.
Claims Coverage
The provided claim set centers on one independent compound claim for formula (I) and related dependent refinements. The inventive features are focused on the formula (I) scaffold with defined binding moiety L, rhamnose F, and specified spacer/linker selections (S1, S2, X1, Y1, and Y2), together with integer constraints and narrowing to particular L members and composition/salt embodiments.
Compound of formula (I) with cationic anti-microbial peptide binding moiety L linked to X1 by an amine
A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L is a binding moiety representing a cationic anti-microbial peptide linked to X1 by an amine, with F representing rhamnose and with structural selection parameters S1, S2, X1, Y1, Y2, and integer variables as stated.
Spacer S1 selected from specified bond or spacer groups with optional amide or urethane substitution
S1 is a bond or a spacer selected from the listed chain structures, wherein one or two CH2 groups may optionally be substituted by a C(O)NH or NHC(O) group, with the corresponding integer ranges as stated.
Spacer S2 selected from specified bond or spacer groups with optional amide or urethane substitution
S2 is a spacer selected from the listed chain structures, wherein one or two CH2 groups may optionally be substituted by a C(O)NH or NHC(O) group, with the corresponding integer ranges as stated.
Link connectivity defined by X1, Y1, Y2, and biphenyl Cy placement
X1 is a bond or C(O)-Y1, Y1 and Y2 independently represent a bond or selected functional groups including O, S, NH, C(O), NHC(O), or C(O)NH, and Cy is biphenyl such that the Y1-S1-X1 group and the [F-S2-Y2]m group or groups are present on either phenyl ring.
L selected to a specified set of polymyxin or lipopeptide members
L is a lipopeptide or a polymyxin selected from Polymyxin B, Polymyxin B2, Polymyxin Nonapeptide, Colistin A, Colistin B, or additional compounds shown in the figures, or derivatives thereof.
Claim coverage centers on the formula (I) scaffold that couples a cationic anti-microbial peptide binding moiety L to rhamnose F through an amine-linked X1 connection. The claim refinements restrict spacer and linker classes, define the Y1/Y2 functional-group options and Cy placement, and narrow L to specified polymyxin or lipopeptide members, with pharmaceutical composition and pharmaceutically acceptable salt embodiments also covered.
Stated Advantages
Promotes complement activation.
Promotes phagocytosis.
Promotes killing of bacteria.
Reduced likelihood of resistance due to lipid A binding.
Documented Applications
Flow cytometric IgG recruitment assessment for anti-rhamnose IgG interaction using Pseudomonas aeruginosa PA01 in the presence of Example compounds, with reported fold-change values.
Flow cytometric human serum complement deposition assessment of C3b/iC3b on E. coli K1:O18ac:H7 in the presence of Example compounds, with reported fold-change values.
Mass spectrometry and LCMS characterization for Examples 4–6 and reference examples 7–11, including illustrated chemical structures.
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