Penicillin-binding protein inhibitors
Inventors
Burns, Christopher J. • DAIGLE, Denis • Chu, Guo-Hua • HAMRICK, Jodie • Lucas, Matthew • Boyd, Steven A. • Zulli, Allison L. • Mesaros, Eugen F. • Condon, Stephen M. • TROUT, Robert E. Lee • MYERS, Cullen L.
Assignees
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Publication Number
US-11332485-B2
Publication Date
2022-05-17
Expiration Date
Abstract
Described herein are certain boron-containing compounds, compositions, preparations and their use as modulators of the transpeptidase function of bacterial penicillin-binding proteins and as antibacterial agents. In some embodiments, the compounds described herein inhibit penicillin-binding proteins. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.
Core Innovation
The disclosure defines compounds of Formula (VIa) or (VIb), or pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer forms. The compounds are defined by Ring A as thiazole, together with linker units L1, L2, and L3 and extensive variable substituent positions, including R1, R2, Z, Y, and other R groups, with many options for ring formation and optional substitution.
The structural definition includes L1 and L2 as -(CR1R2)n- and -(CR1R2)m-, and L3 as C(=O), S(=O), or S(=O)2. The substituent scope includes hydrogen, halogen, optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, thioether, amino, amide-like, and carbonyl-containing groups, with options for two substituents to be taken together to form a ring.
The chemical space is further defined by Z and Y substituent sets, including boron-associated motifs and cyclic boronate ester formation when two X groups or two Y groups together with boron form a cyclic boronate ester. The definition also includes T selected from pyridin-1-yl, pyrimidin-1-yl, or thiazol-3-yl, Q as a pharmaceutically acceptable counterion, and parameter ranges such as n, m, p, q, v, and w.
Claims Coverage
The consolidated claim coverage includes one independent claim covering a broad compound genus of Formula (VIa) or (VIb) and its pharmaceutically acceptable forms. The inventive scope is organized around Ring A fixed as thiazole, defined linker structures L1-L3, and extensive substituent variability across R positions, Z, and Y, including boronate ester options and parameter constraints.
Thiazole-containing formula (VIa)/(VIb) scaffold
A compound of Formula (VIa) or (VIb), or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof, wherein Ring A is thiazole and L1, L2, and L3 are defined by the stated linker patterns.
Extensive substituent variability across R positions
The compound defines multiple substituent positions, including R1, R2, R8, R20/R21, R22/R23, R24/R25, R30/R31, R32/R33, R50/R51, R52/R53, R74, and R82/R83, with allowed options including hydrogen, halogen, optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, thioether, amino, amide-like, and carbonyl-containing groups, plus ring-forming combinations.
Boron-associated Z and Y definitions with cyclic boronate ester options
Z and Y are defined through broad functional-group sets, including boron-associated substituent forms and the option for cyclic boronate ester formation when substituent groups are taken together with boron.
Parameter and counterion constraints
The compound definition includes ranges for n, m, p, q, v, and w, T selected from pyridin-1-yl, pyrimidin-1-yl, or thiazol-3-yl, and Q as a pharmaceutically acceptable counterion.
Treatment of bacterial infection by administering the compound
A method of treating a bacterial infection in a subject by administering an effective amount of the compound in pharmaceutically acceptable form.
The claim coverage centers on a broad genus of thiazole-containing Formula (VIa)/(VIb) compounds with defined linker structure, extensive substituent options, boronate ester-related definitions, and parameter constraints. The consolidated set also includes a method claim for treating a bacterial infection by administering an effective amount of the claimed compound forms.
Stated Advantages
The compounds inhibit penicillin-binding proteins.
Antibacterial activity, including against beta-lactamase-mediated resistance.
Modulates beta-lactamase.
Inhibits beta-lactamase.
Used for treating bacterial infections.
Similar MIC behavior is reported for boronate PBP inhibitors in the CTX-M15 beta-lactamase producing E. coli context, while beta-lactam antibiotics are described as having weakened activity.
Documented Applications
Treating a bacterial infection in a subject by administering an effective amount of a compound as defined in claim 1.
Pharmaceutical compositions comprising the defined compounds or their forms.
Inhibiting bacterial PBP activity in a human.
Treating bacterial infections, including upper respiratory tract infection, lower respiratory tract infection, urinary tract infection, intra-abdominal infection, and skin infection.
Parenteral pharmaceutical compositions and oral tablet/capsule formulations for compounds of the described formulas.
Binding assays for penicillin-binding proteins using Bocillin-FL competition, fluorescence polarization competition for PBP3, and radioligand competition with a labeled boronic acid probe for PBP1a/1b.
Microbiological activity assessment via MIC results against S. aureus and E. coli strains, including evaluation in a CTX-M15 beta-lactamase producing E. coli context.
A method of treating a bacterial infection in a subject by administering an effective amount of the compound.
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