Discovery of an Orally Available Diazabicyclooctane Inhibitor (ETX0282) of Class A, C, and D Serine β-Lactamases

Thomas F.  Durand-Réville; Janelle  Comita-Prevoir; Jing  ZhangXiaoyun  WuTricia L.  May-DrackaJan Antoinette C.  RomeroFrank  WuApril  ChenAdam B.  ShapiroNicole M.  CarterSarah M.  McLeodRobert A.  GiacobbeJeroen C.  VerheijenSushmita D.  LahiriMichael D.  SaccoYu  ChenJohn P.  O’DonnellAlita A.  MillerJohn P.  MuellerRubén A.  Tommasi

首页> 外文期刊>Journal of Medicinal Chemistry >Discovery of an Orally Available Diazabicyclooctane Inhibitor (ETX0282) of Class A, C, and D Serine β-Lactamases

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Discovery of an Orally Available Diazabicyclooctane Inhibitor (ETX0282) of Class A, C, and D Serine β-Lactamases

机译：Discovery of an Orally Available Diazabicyclooctane Inhibitor (ETX0282) of Class A, C, and D Serine β-Lactamases

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Multidrug resistant Gram-negative bacterial infections are an increasing public health threat due to rapidly rising resistance toward β-lactam antibiotics. The hydrolytic enzymes called β-lactamases are responsible for a large proportion of the resistance phenotype. β-Lactamase inhibitors (BLIs) can be administered in combination with β-lactam antibiotics to negate the action of the β-lactamases, thereby restoring activity of the β-lactam. Newly developed BLIs offer some advantage over older BLIs in terms of enzymatic spectrum but are limited to the intravenous route of administration. Reported here is a novel, orally bioavailable diazabicyclooctane (DBO) β-lactamase inhibitor. This new DBO, ETX1317, contains an endocyclic carbon–carbon double bond and a fluoroacetate activating group and exhibits broad spectrum activity against class A, C, and D serine β-lactamases. The ester prodrug of ETX1317, ETX0282, is orally bioavailable and, in combination with cefpodoxime proxetil, is currently in development as an oral therapy for multidrug resistant and carbapenem-resistant Enterobacterales infections.

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《Journal of Medicinal Chemistry》 |2020年第21期|12511-12525|共15页
作者
Thomas F. Durand-Réville; Janelle Comita-Prevoir; Jing ZhangXiaoyun WuTricia L. May-DrackaJan Antoinette C. RomeroFrank WuApril ChenAdam B. ShapiroNicole M. CarterSarah M. McLeodRobert A. GiacobbeJeroen C. VerheijenSushmita D. LahiriMichael D. SaccoYu ChenJohn P. O’DonnellAlita A. MillerJohn P. MuellerRubén A. Tommasi;
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作者单位

Infection Discovery, AstraZeneca R&D Boston;

Entasis Therapeutics;

Department of Molecular Medicine, Morsani College of Medicine, University of South Florida;

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Discovery of an Orally Available Diazabicyclooctane Inhibitor (ETX0282) of Class A, C, and D Serine β-Lactamases

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