Optimization of LpxC Inhibitors for Antibacterial Activity and Cardiovascular Safety

ChemMedChem. 2019 Aug 20;14(16):1560-1572. doi: 10.1002/cmdc.201900287. Epub 2019 Aug 5.

Abstract

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram-negative bacteria. ACHN-975 (N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose-limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN-975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC-516, (S)-N-(2-(hydroxyamino)-1-(3-methoxy-1,1-dioxidothietan-3-yl)-2-oxoethyl)-4-(6-hydroxyhexa-1,3-diyn-1-yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL-1 for parenteral administration and conversion into the active drug with a t1/2 of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.

Keywords: LpxC; Pseudomonas; amines; antibiotics; inhibitors; prodrugs; zwitterions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Animals
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / pharmacokinetics
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / toxicity
  • Bacterial Proteins / antagonists & inhibitors
  • Cardiotoxicity
  • Diynes / chemical synthesis
  • Diynes / pharmacokinetics
  • Diynes / pharmacology*
  • Diynes / toxicity
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / toxicity
  • Heart / drug effects*
  • Hydroxamic Acids / chemical synthesis
  • Hydroxamic Acids / pharmacokinetics
  • Hydroxamic Acids / pharmacology*
  • Hydroxamic Acids / toxicity
  • Male
  • Molecular Structure
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacokinetics
  • Prodrugs / pharmacology
  • Prodrugs / toxicity
  • Pseudomonas aeruginosa / drug effects
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Diynes
  • Enzyme Inhibitors
  • Hydroxamic Acids
  • Prodrugs
  • Amidohydrolases
  • UDP-3-O-acyl-N-acetylglucosamine deacetylase