Discovery of Cyclic Boronic Acid QPX7728, an Ultrabroad-Spectrum Inhibitor of Serine and Metallo-β-lactamases.

Journal of Medicinal Chemistry
Scott J HeckerMichael N Dudley

Abstract

Despite major advances in the β-lactamase inhibitor field, certain enzymes remain refractory to inhibition by agents recently introduced. Most important among these are the class B (metallo) enzyme NDM-1 of Enterobacteriaceae and the class D (OXA) enzymes of Acinetobacter baumannii. Continuing the boronic acid program that led to vaborbactam, efforts were directed toward expanding the spectrum to allow treatment of a wider range of organisms. Through key structural modifications of a bicyclic lead, stepwise gains in spectrum of inhibition were achieved, ultimately resulting in QPX7728 (35). This compound displays a remarkably broad spectrum of inhibition, including class B and class D enzymes, and is little affected by porin modifications and efflux. Compound 35 is a promising agent for use in combination with a β-lactam antibiotic for the treatment of a wide range of multidrug resistant Gram-negative bacterial infections, by both intravenous and oral administration.

References

Sep 1, 1982·The Biochemical Journal·S G Waley
Sep 1, 1994·Acta Crystallographica. Section D, Biological Crystallography·UNKNOWN Collaborative Computational Project, Number 4
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Sep 23, 2009·Acta Crystallographica. Section D, Biological Crystallography·Nigel W MoriartyPaul D Adams
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·T Geoff G BattyeAndrew G W Leslie
Aug 9, 2011·Methods : a Companion to Methods in Enzymology·Paul D AdamsPeter H Zwart
Apr 7, 2012·Trends in Molecular Medicine·Patrice NordmannLaurent Poirel
Apr 17, 2012·Acta Crystallographica. Section D, Biological Crystallography·Pavel V AfoninePaul D Adams
Jun 26, 2013·Acta Crystallographica. Section D, Biological Crystallography·Philip R Evans, Garib N Murshudov
Mar 18, 2015·Journal of Medicinal Chemistry·Scott J HeckerMichael N Dudley
Aug 21, 2015·Pharmacotherapy·Evan J ZasowskiMichael J Rybak
Jan 25, 2017·Antimicrobial Agents and Chemotherapy·Samuel T CahillJürgen Brem
May 16, 2017·Future Medicinal Chemistry·Ross P McGearyGerhard Schenk
Mar 9, 2018·The Annals of Pharmacotherapy·Jonathan C ChoJoe Pardo
Aug 28, 2019·Journal of Medicinal Chemistry·Alen KrajncChristopher J Schofield
Sep 5, 2019·Journal of Medicinal Chemistry·Orville A PembertonYu Chen

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Citations

Jun 7, 2020·Biomolecules·Antonella R PalaciosAlejandro J Vila
Oct 1, 2020·Dalton Transactions : an International Journal of Inorganic Chemistry·Cheng Chen, Kewu Yang
Jul 29, 2020·The Journal of Microbiology·Shivakumar S Jalde, Hyun Kyung Choi
Mar 28, 2020·International Journal of Environmental Research and Public Health·Yanling WangJianfeng Wang
May 1, 2020·Biomolecules·Scott T LefurgyRobert A Bonomo
May 13, 2020·Expert Opinion on Therapeutic Patents·Nakita ReddyTricia Naicker
Sep 25, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mariana Pereira SilvaMaria Emília Sousa
Dec 10, 2020·International Journal of Molecular Sciences·Juan C Vázquez-UchaAlejandro Beceiro
Jan 22, 2021·Bioorganic & Medicinal Chemistry Letters·Qidi Kong, Yushe Yang
Apr 1, 2021·Accounts of Chemical Research·David T Davies, Martin Everett
Mar 22, 2021·Bioorganic & Medicinal Chemistry Letters·Yu-Hang YanYou-Cai Xiao
Sep 17, 2020·European Journal of Medicinal Chemistry·Laurent GavaraJean-François Hernandez
May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Alexandra V Krivitskaya, Maria G Khrenova
Jun 12, 2021·Bioorganic Chemistry·Laurent GavaraJean-François Hernandez
Jul 6, 2021·European Journal of Medicinal Chemistry·Ting WangJianyou Shi
Jul 6, 2021·JAC-antimicrobial Resistance·David M Livermore
Jul 12, 2021·The Lancet Infectious Diseases·Maria F MojicaRobert A Bonomo
Aug 7, 2021·Infectious Diseases and Therapy·Balaji VeeraraghavanRani Diana Sahni
Aug 15, 2021·European Journal of Medicinal Chemistry·Kalyan C Nagulapalli VenkataSiddharth K Tripathi
Jul 14, 2020·Journal of Medicinal Chemistry·Thomas F Durand-RévilleRubén A Tommasi
Sep 7, 2021·Frontiers in Cellular and Infection Microbiology·Gopalakrishnan ThamilselvanAdline Princy Solomon
Oct 12, 2021·Organic Letters·Oliver Andler, Uli Kazmaier
Sep 10, 2021·Chemistry : a European Journal·Dmitriy M VolochnyukOleksandr O Grygorenko

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