Benzoxaborole compounds and uses thereof

a technology of benzoxaborole and compounds, applied in the field of new boron-containing molecules, can solve the problems of no longer editing mischarged amino acids, affecting the synthesis of proteins, and affecting the synthesis of proteins, and achieve the effect of reducing the resistance ra

Inactive Publication Date: 2015-03-19
ANACOR PHARMA INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007]Embodiments of the present invention feature combinations of norvaline and / or other amino acids with certain substituted benzoxaboroles, such as those described in U.S. Pat. No. 7,816,344 (the contents of which are hereby incorporated by reference herein in their entirety) for use in the treatment of bacterial infections in animal subjects. In particular embodiments, such benzoxaboroles are used, in combination with an amino acid or amino acid salt, to decrease the rate of resistance to such substituted benzoxaboroles, in an animal subject with a bacterial infection, particularly in an animal subject with a Gram negative (−) bacterial infection.

Problems solved by technology

Mischarged tRNALeu are deleterious to the cell.
This blocks tRNALeu from being aminoacylated, which ultimately leads to the inhibition of protein synthesis.
However, it can no longer edit mischarged amino acids.

Method used

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  • Benzoxaborole compounds and uses thereof
  • Benzoxaborole compounds and uses thereof
  • Benzoxaborole compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

Resistant Mutants to GSK2251052 Generated In Vitro

[0111]Spontaneous Resistance Frequency was determined in vitro for GSK2251052 and the resistance mutants in E. coli ATCC 25922, K. pneumoniae ATCC 13883, and P. aeruginosa ATCC 27853 strains were characterized. GSK2251052 was prepared as described in U.S. Pat. No. 7,816,344 (the entire contents of which are hereby incorporated by reference herein). LB broth, Mueller Hinton II broth (adjusted), and Difco noble agar were obtained from Becton Dickinson (Cockeysville, Md., USA). M9 minimal broth containing 1×M9 salt, 0.5 μg / ML thiamine, 1 mM MgSO4, 0.1 mM CaCl2, 2% glucose, was obtained from Teknova (Hollister, Calif., USA). Antibacterial agents ciprofloxacin, ceftazidime, chloramphenicol, gentamycin, kanamycin, polymixin B, tobramycin and trimethoprim, and amino acids were obtained from Sigma Chemicals (St. Louis, Mo., USA). Strains were obtained from ATCC (Manassas, Va., USA).

[0112]Determination of the Minimum Inhibitory Concentration....

example 2

Resistant Mutants to GSK2251052 Generated In Vivo

[0130]A comparative, dose-ranging study of GSK2251052 vs. imipenem-cilastatin in complicated lower urinary tract infection and pyelonephritis was undertaken with 210 targeted patients (20 actually enrolled) in a phase II clinical trial. The study was designed to determine the appropriate and safe dose for Phase III trials. Doses were 750 mg or 1500 mg twice a day, compared to an active comparator, with an independent safety review committee.

[0131]The phase II clinical trial identified four subjects who developed spontaneous resistance to GSK2251052 as evidenced by increased MICs (>32-fold) determined for the clinical isolates from the four subjects. Two of the resistant mutant strains identified were E. coli strains, one was a P. mirabilis strain, and one was a K. pneumoniae strain. The rates of spontaneous resistance for the baseline isolates tested were not significantly different from standard strains previously tested (˜10−7).

[013...

example 3

Measurement of the Suppression of the Emergence of a Resistant Bacterial Strain In Vitro

[0142]Clinical strains of Escherichia coli and Proteus mirabilis isolated from the above-described clinical trial study (Table 12), along with other E. coli strains were used to measure the suppression of the emergence of resistant bacterial strains in vitro and to determine the susceptibility of these GSK2251052 resistant bacterial isolates to norvaline. Increased sensitivity to this leucine analog would suggest an editing domain mutation in LeuRS. Moreover, in order to find out if sub-inhibitory concentrations of norvaline could suppress growth of GSK2251052 resistant mutants under restricted amino acid conditions in the laboratory, the frequency of spontaneous resistance to GSK2251052 was determined for Escherichia coli 1162222 (standard strain) and the E. coli isolate (baseline strain from subject E. coli 1, isolated from blood in the above-described clinical study in Example 2) in the presen...

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Abstract

Norvaline and/or other amino acids that are capable of being acylated onto tRNALeu by LeuRS, in combination with substituted benzoxaboroles, such as a compound having a structure according to formula III: and methods for decreasing the frequency of resistance and/or reducing the rate of resistance and/or suppressing the emergence of resistance that develops in bacteria exposed to a substituted benzoxaborole or salt thereof by administering a combination of a substituted benzoxaborole such as a compound of formula III or salt thereof and an amino acid or a salt thereof.

Description

PRIORITY[0001]This application is a Patent Cooperation Treaty Application and claims priority from U.S. Application Ser. No. 61 / 624,294 filed Apr. 14, 2012, the contents of which are hereby incorporated by reference herein in their entirety.GOVERNMENT LICENSE RIGHTS[0002]This invention was made with US Government support under HHSO100201100016C awarded by BARDA. The US Government has certain rights in the invention.FIELD OF THE INVENTION[0003]The present invention relates to the use of a novel class of boron-containing molecules which bind to the editing domain of leucyl-tRNA synthetase (LeuRS), and more particularly relates to such novel class of boron-containing molecules in combination with amino acids and / or amino acid salts for treatment of bacterial infections in animal subjects.BACKGROUND ART[0004]The global rise of bacteria and other microorganisms resistant to antibiotics and antimicrobials in general, poses a major threat. Deployment of massive quantities of antimicrobial ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/69A61K31/198
CPCA61K31/198A61K31/69Y02A50/30A61K2300/00
Inventor ALLEY, MICHAEL RICHARD KEVINWIDDOWSON, KATHERINE
Owner ANACOR PHARMA INC
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