Inhibition of tissue plasminogen activator (unknown origin) using GK-pNA as substrate preincubated for 10 mins followed by substrate addition measured for 30 mins by spectrophotometric analysis
- Deposit:2016-12-22
- Modify:2020-06-24
Title: Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases.
Abstract: The increasing dissemination of carbapenemases in Gram-negative bacteria has threatened the clinical usefulness of the β-lactam class of antimicrobials. A program was initiated to discover a new series of serine β-lactamase inhibitors containing a boronic acid pharmacophore, with the goal of finding a potent inhibitor of serine carbapenemase enzymes that are currently compromising the utility of the carbapenem class of antibacterials. Potential lead structures were screened in silico by modeling into the active sites of key serine β-lactamases. Promising candidate molecules were synthesized and evaluated in biochemical and whole-cell assays. Inhibitors were identified with potent inhibition of serine carbapenemases, particularly the Klebsiella pneumoniae carbapenemase (KPC), with no inhibition of mammalian serine proteases. Studies in vitro and in vivo show that RPX7009 (9f) is a broad-spectrum inhibitor, notably restoring the activity of carbapenems against KPC-producing strains. Combined with a carbapenem, 9f is a promising product for the treatment of multidrug resistant Gram-negative bacteria.
Journal: J Med Chem
Year: 2015
Volume: 58
Issue: 9
First Page: 3682
Last Page: 3692
DOI: 10.1021/acs.jmedchem.5b00127
Target ChEMBL ID: CHEMBL1873
ChEMBL Target Name: Tissue-type plasminogen activator
ChEMBL Target Type: SINGLE PROTEIN - Target is a single protein chain
Relationship Type: D - Direct protein target assigned
Confidence: Direct single protein target assigned
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