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Discovery of VNRX-7145 (VNRX-5236 Etzadroxil): An Orally Bioavailable ß-Lactamase Inhibitor for Enterobacterales Expressing Ambler Class A, C, and D Enzymes.
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.
Afiliação
  • Trout RE; Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
  • Zulli A; Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
  • Mesaros E; Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
  • Jackson RW; Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
  • Boyd S; Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
  • Liu B; Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
  • Hamrick J; Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
  • Daigle D; Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
  • Chatwin CL; Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
  • John K; Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
  • McLaughlin L; Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
  • Cusick SM; Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
  • Weiss WJ; UNT System College of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, Texas 76107-2699, United States.
  • Pulse ME; UNT System College of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, Texas 76107-2699, United States.
  • Pevear DC; Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
  • Moeck G; Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
  • Xerri L; Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
  • Burns CJ; Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
J Med Chem ; 64(14): 10155-10166, 2021 07 22.
Article em En | MEDLINE | ID: mdl-34191513
A major antimicrobial resistance mechanism in Gram-negative bacteria is the production of ß-lactamase enzymes. The increasing emergence of ß-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 ß-lactamase inhibitor 5 (VNRX-5236). In vitro and in vivo studies demonstrated that 5 restored the activity of the oral cephalosporin antibiotic ceftibuten against Enterobacterales expressing Ambler class A extended-spectrum ß-lactamases, class A carbapenemases, class C cephalosporinases, and class D oxacillinases.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Beta-Lactamases / Enterobacteriaceae / Descoberta de Drogas / Inibidores de beta-Lactamases / Antibacterianos Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Beta-Lactamases / Enterobacteriaceae / Descoberta de Drogas / Inibidores de beta-Lactamases / Antibacterianos Idioma: En Ano de publicação: 2021 Tipo de documento: Article