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Discovery of piperazic acid peptide deformylase inhibitors with in vivo activity for respiratory tract and skin infections.

Abstract
The discovery of a novel series of peptide deformylase inhibitors incorporating a piperazic acid amino acid found in nature is described. These compounds demonstrated potent in vitro enzymatic potency and antimicrobial activity. Crystal structure analysis revealed the piperazic acid optimized a key contact with the PDF protein that accounted for the increased enzymatic potency of these compounds. We describe lead optimization of the P3' region of the series that resulted in a compound with good potency against three target organisms. One molecule showed in vivo efficacy in a rat respiratory infection model but ultimately did not meet candidate progression criteria.
AuthorsJared T Spletstoser, Jason Dreabit, Andrew N Knox, Andrew Benowitz, Nino Campobasso, Paris Ward, Guanglei Cui, Thomas Lewandowski, Lynn McCloskey, Kelly M Aubart
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 29 Issue 16 Pg. 2410-2414 (08 15 2019) ISSN: 1464-3405 [Electronic] England
PMID31160176 (Publication Type: Journal Article)
CopyrightCopyright © 2019 Elsevier Ltd. All rights reserved.
Chemical References
  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Pyridazines
  • piperazic acid
  • Amidohydrolases
  • peptide deformylase
Topics
  • Amidohydrolases (antagonists & inhibitors, metabolism)
  • Anti-Bacterial Agents (chemical synthesis, chemistry, pharmacology)
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery
  • Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Haemophilus influenzae (drug effects, enzymology)
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Pyridazines (chemical synthesis, chemistry, pharmacology)
  • Respiratory Tract Infections (drug therapy, metabolism)
  • Skin Diseases, Infectious (drug therapy, metabolism)
  • Staphylococcus aureus (drug effects, enzymology)
  • Streptococcus pneumoniae (drug effects, enzymology)
  • Structure-Activity Relationship

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