Discovery of VNRX-7145 (VNRX-5236 Etzadroxil): An Orally Bioavailable β-Lactamase Inhibitor for Enterobacterales Expressing Ambler Class A, C, and D Enzymes

Robert E. Trout, Allison Zulli, Eugen Mesaros, Randy W. Jackson, Steven Boyd, Bin Liu, Jodie Hamrick, Denis Daigle, Cassandra L. Chatwin, Kaitlyn John, Lisa McLaughlin, Susan M. Cusick, William J. Weiss, Mark E. Pulse, Daniel C. Pevear, Greg Moeck, Luigi Xerri, Christopher J. Burns

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4 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)10155-10166
Number of pages12
JournalJournal of Medicinal Chemistry
Volume64
Issue number14
DOIs
StatePublished - 22 Jul 2021

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