- Discovery of VNRX-7145 (VNRX-5236 Etzadroxil): An Orally Bioavailable β-Lactamase Inhibitor for Enterobacterales Expressing Ambler Class A, C, and D Enzymes
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A major antimicrobial resistance mechanism in Gram-negative bacteria is the production of β-lactamase enzymes. The increasing emergence of β-lactamase-producing multi-drug-resistant “superbugs” has resulted in increases in costly hospital Emergency Department (ED) visits and hospitalizations due to the requirement for parenteral antibiotic therapy for infections caused by these difficult-to-treat bacteria. To address the lack of outpatient treatment, we initiated an iterative program combining medicinal chemistry, biochemical testing, microbiological profiling, and evaluation of oral pharmacokinetics. Lead optimization focusing on multiple smaller, more lipophilic active compounds, followed by an exploration of oral bioavailability of a variety of their respective prodrugs, provided 36 (VNRX-7145/VNRX-5236 etzadroxil), the prodrug of the boronic acid-containing β-lactamase inhibitor 5 (VNRX-5236).In vitroandin vivostudies demonstrated that 5 restored the activity of the oral cephalosporin antibiotic ceftibuten against Enterobacterales expressing Ambler class A extended-spectrum β-lactamases, class A carbapenemases, class C cephalosporinases, and class D oxacillinases.
- Trout, Robert E.,Zulli, Allison,Mesaros, Eugen,Jackson, Randy W.,Boyd, Steven,Liu, Bin,Hamrick, Jodie,Daigle, Denis,Chatwin, Cassandra L.,John, Kaitlyn,McLaughlin, Lisa,Cusick, Susan M.,Weiss, William J.,Pulse, Mark E.,Pevear, Daniel C.,Moeck, Greg,Xerri, Luigi,Burns, Christopher J.
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- PENICILLIN-BINDING PROTEIN INHIBITORS
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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 describ
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Paragraph 00147; 00151
(2021/06/04)
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- PENICILLIN-BINDING PROTEIN INHIBITORS
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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 describ
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Paragraph 00185; 00196; 00203
(2019/12/15)
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- BORON-CONTAINING COMPOUNDS
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Described herein are boron-containing compounds, compositions, and methods for their preparation.
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Paragraph 00122
(2018/03/28)
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- BETA-LACTAMASE INHIBITORS
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Described herein are compounds and compositions that modulate the activity of beta -lactamases. In some embodiments, the compounds described herein inhibit beta-lactamase. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.
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- BETA-LACTAMASE INHIBITORS
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Described herein are compounds and compositions that modulate the activity of beta-lactamases. In some embodiments, the compounds described herein inhibit beta-lactamase. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.
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Paragraph 00446
(2017/07/04)
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- BETA-LACTAMASE INHIBITORS
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Described herein are compounds and compositions that modulate the activity of beta-lactamases. In some embodiments, the compounds described herein inhibit beta-lactamase. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.
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Paragraph 00313
(2014/06/24)
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- BETA-LACTAMASE INHIBITORS
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Described herein are compounds and compositions that modulate the activity of beta-lactamases. In some embodiments, the compounds described herein inhibit beta-lactamase. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.
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Paragraph 0470
(2014/07/22)
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- BETA-LACTAMASE INHIBITORS
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Disclosed herein are α-aminoboronic acids and their derivatives which act as inhibitors of beta-lactamases. Also disclosed herein are pharmaceutical compositions comprising α-aminoboronic acids and methods of use thereof.
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