Polymyxin compounds and uses thereof
Inventors
Brown, Pamela • Dawson, Michael • Simonovic, Mona • Boakes, Steven • Duperchy, Esther • Stanway, Steven James • Wilson, Antoinette • Moss, Stephen Frederick
Assignees
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Publication Number
US-12146004-B2
Publication Date
2024-11-19
Expiration Date
Abstract
The present invention provides a compound of formula (I), and its use in methods of treatment, including the treatment of bacterial infections. Methods for the preparation of the compound of formula (I) are also provided. The compound of formula (I) has the structure shown below, where —R6 and —R7 are each together with the carbonyl group and nitrogen alpha to the carbon to which it is attached an amino acid residue, except that R6 together with the carbonyl group and nitrogen alpha to the carbon to which it is attached is not a phenylalanine, leucine or valine residue and/or —R7 together with the carbonyl group and nitrogen alpha to the carbon to which it is attached is not a leucine, iso-leucine, phenylalanine, threonine, valine or nor-valine residue, and -T, -A1, -A2, -A3 and —R10 are as discussed in the application:
Core Innovation
The document concerns compounds of formula (I) in which A1 is absent, A2 is an amino acid residue selected from threonine and serine, and X is selected from C(O), NHC(O), OC(O), CH2, or SO2. The compounds are polymyxin-derived peptide analogs and include salts, protected forms, and/or prodrug forms.
The structural definitions further constrain A3, R3, RT, RC, RD, RN, RNA, LB, LC, LN, and LAA, with allowed covalent bonds or selected linking motifs and substituent classes. RT is an amino-containing group that is guanidine or forms a 5-to 10-membered nitrogen-containing monocyclic or bicyclic heterocycle, optionally substituted and optionally containing one further nitrogen, oxygen, or sulfur ring atom, with optional oxo substitution on a ring carbon atom.
The partial content also describes polymyxin B heptapeptide and nonapeptide analogs, including L-Thr-L-Dap motif variants, stereoisomer labels, modified N-terminal acyl and side-chain groups, and exemplified analogs characterized by chemical structure depictions, molecular formulae, mass spectrometric indicators, and HPLC retention time.
Claims Coverage
The consolidated claim coverage centers on formula (I) compounds with A1 absent, A2 selected from threonine or serine, X restricted to specified linkage types, and RT defined as guanidine or a substituted 5-to 10-membered nitrogen-containing monocyclic or bicyclic heterocycle, together with detailed substituent and linking-group definitions. The claims also include selection claims based on T-A2-A3-R6 expressions and expressly encompass salts, protected forms, and/or prodrug forms.
Formula (I) polymyxin-derived compound scaffold
A compound of formula (I) wherein A1 is absent, A2 is an amino acid residue selected from threonine and serine, A3 is defined with R3 as C1-6 alkyl having one amino or one hydroxyl substituent, and X is selected from C(O), NHC(O), OC(O), CH2, or SO2.
Amino-containing RT group as guanidine or nitrogen heterocycle
RT is an amino-containing group that is either guanidine or forms a 5-to 10-membered nitrogen-containing monocyclic or bicyclic heterocycle, optionally substituted and optionally containing one further nitrogen, oxygen, or sulfur ring atom, with optional oxo substitution on a ring carbon atom.
Defined linking-group and substituent framework
The claims define linking-group classes and substituent options for RC, RD, RN, RNA, LB, LC, LN, and LAA, including covalent bonds or selected linking motifs and residue constraints for R6, R7, and R10.
Selection claim based on T-A2-A3-R6
A compound selected from the group consisting of compounds and salts thereof in which T-A2-A3-R6 is defined by the claimed formula expression.
Salt, protected form, and prodrug coverage
The claims expressly include the compounds as salts, protected forms, and/or prodrug forms.
Across the independent claims, the inventive coverage is a polymyxin-derived formula (I) scaffold with residue restrictions at A2 and A3, defined linkage types at X, an RT group that is guanidine or a constrained nitrogen-containing mono- or bicyclic heterocycle, additional substituent and residue constraints, and explicit coverage of salts, protected forms, and/or prodrug forms.
Stated Advantages
Purported reduction in toxicity relative to polymyxin B/colistin, including nephrotoxicity and neurotoxicity.
Maintained or improved antimicrobial activity versus polymyxin B/colistin.
Activity against multidrug-resistant and polymyxin-resistant strains.
Improved potency against polymyxin-resistant strains.
A log P ranges are associated with desired activity/safety profiles.
Documented Applications
Treating and/or prophylaxis of microbial infections, particularly Gram-negative bacterial infections.
Treatment of Gram-negative bacterial infection in a patient by administering the compound or a salt form.
Use in combination therapy with a second agent such as rifampicin.
Antimicrobial susceptibility assays against Gram-negative pathogens, including Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii.
Pharmaceutical composition containing the claimed compound or a salt form of the compound.
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