Discovery of MK-7655, a β-lactamase inhibitor for combination with Primaxin®

Bioorg Med Chem Lett. 2014 Feb 1;24(3):780-5. doi: 10.1016/j.bmcl.2013.12.101. Epub 2014 Jan 3.

Abstract

β-Lactamase inhibitors with a bicyclic urea core and a variety of heterocyclic side chains were prepared and evaluated as potential partners for combination with imipenem to overcome class A and C β-lactamase mediated antibiotic resistance. The piperidine analog 3 (MK-7655) inhibited both class A and C β-lactamases in vitro. It effectively restored imipenem's activity against imipenem-resistant Pseudomonas and Klebsiella strains at clinically achievable concentrations. A combination of MK-7655 and Primaxin® is currently in phase II clinical trials for the treatment of Gram-negative bacterial infections.

Keywords: Antibacterial; Antibiotic; Imipenem; MK-7655; β-Lactamase inhibitor.

MeSH terms

  • Azabicyclo Compounds / chemistry*
  • Azabicyclo Compounds / pharmacology*
  • Cilastatin / chemistry*
  • Cilastatin / pharmacology
  • Cilastatin, Imipenem Drug Combination
  • Crystallography, X-Ray
  • Drug Combinations
  • Drug Discovery*
  • Drug Resistance, Bacterial / drug effects
  • Enzyme Inhibitors / chemistry*
  • Imipenem / chemistry*
  • Imipenem / pharmacology
  • Inhibitory Concentration 50
  • Klebsiella / drug effects
  • Microbial Sensitivity Tests
  • Models, Biological
  • Pseudomonas / drug effects
  • Structure-Activity Relationship
  • beta-Lactamase Inhibitors*

Substances

  • Azabicyclo Compounds
  • Drug Combinations
  • Enzyme Inhibitors
  • beta-Lactamase Inhibitors
  • Cilastatin
  • Imipenem
  • Cilastatin, Imipenem Drug Combination
  • relebactam