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

  • J Med Chem. 2020 Jul 23;63(14):7491-7507. doi: 10.1021/acs.jmedchem.9b01976.
Scott J Hecker  1 ,  K Raja Reddy  1 ,  Olga Lomovskaya  1 ,  David C Griffith  1 ,  Debora Rubio-Aparicio  1 ,  Kirk Nelson  1 ,  Ruslan Tsivkovski  1 ,  Dongxu Sun  1 ,  Mojgan Sabet  1 ,  Ziad Tarazi  1 ,  Jonathan Parkinson  1 ,  Maxim Totrov  2 ,  Serge H Boyer  1 ,  Tomasz W Glinka  1 ,  Orville A Pemberton  3 ,  Yu Chen  3 ,  Michael N Dudley  1
Affiliations
  • 1. Qpex Biopharma, Inc., 6275 Nancy Ridge Drive, Suite 100, San Diego, California 92121, United States.
  • 2. Molsoft LLC, 11199 Sorrento Valley Road, San Diego, California 92121, United States.
  • 3. Department of Molecular Medicine, University of South Florida Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, Florida 33612, United States.
PMID: 32150407 DOI: 10.1021/acs.jmedchem.9b01976
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.

Products