Broad-spectrum cyclic boronate β-lactamase inhibitors featuring an intramolecular prodrug for oral bioavailability

  • Bioorg Med Chem. 2022 May 15;62:116722. doi: 10.1016/j.bmc.2022.116722.
K Raja Reddy  1 ,  Maxim Totrov  2 ,  Olga Lomovskaya  1 ,  David C Griffith  1 ,  Ziad Tarazi  1 ,  Matthew C Clifton  3 ,  Scott J Hecker  4
Affiliations
  • 1. Qpex Biopharma, Inc, 6275 Nancy Ridge Dr., Suite 100, San Diego, CA 92121, United States.
  • 2. Molsoft L.L.C, 11199 Sorrento Valley Road, San Diego, CA 92121, United States.
  • 3. Beryllium Discovery, 3 Preston Court, Bedford, MA 01730, United States.
  • 4. Qpex Biopharma, Inc, 6275 Nancy Ridge Dr., Suite 100, San Diego, CA 92121, United States. Electronic address: [email protected].
PMID: 35358864 DOI: 10.1016/j.bmc.2022.116722
Abstract

Early efforts to broaden the spectrum and potency of cyclic boronic acid β-lactamase inhibitor vaborbactam included a series of 7-membered ring boronates. Exploration of stereoisomers and incorporation of heteroatoms allowed identification of the all-carbon cyclic boronate with substituents trans as the preferred core structure, showing inhibition of Class A and C Enzymes. Crystal structures of one analog bound to important β-lactamase Enzymes were obtained. When isolated under acidic conditions, these compounds spontaneously formed a neutral cyclic anhydride (intramolecular prodrug) which was shown to have much-improved oral bioavailability (52-69%) compared to the ring-opened carboxylate salt (9%).

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