Urea-based inhibitors of Trypanosoma brucei methionyl-tRNA synthetase: selectivity and in vivo characterization.

Abstract

Urea-based methionyl-tRNA synthetase inhibitors were designed, synthesized, and evaluated for their potential toward treating human African trypanosomiasis (HAT). With the aid of a homology model and a structure-activity-relationship approach, low nM inhibitors were discovered that show high selectivity toward the parasite enzyme over the closest human homologue. These compounds inhibit parasite growth with EC(50) values as low as 0.15 μM while having low toxicity to mammalian cells. Two compounds (2 and 26) showed excellent membrane permeation in the MDR1-MDCKII model and encouraging oral pharmacokinetic properties in mice. Compound 2 was confirmed to enter the CNS in mice. Compound 26 had modest suppressive activity against Trpanosoma brucei rhodesiense in the mouse model, suggesting that more potent analogues or compounds with higher exposures need to be developed. The urea-based inhibitors are thus a promising starting point for further optimization toward the discovery of orally available and CNS active drugs to treat HAT.

• Authors: Sayaka Shibata, J Robert Gillespie, Ranae M Ranade, Cho Yeow Koh, Jessica E Kim, Joy U Laydbak, Frank H Zucker, Wim G J Hol, Christophe L M J Verlinde, Frederick S Buckner, Erkang Fan
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 14 Pg. 6342-51 (Jul 26 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22720744 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Aminoquinolines
• Enzyme Inhibitors
• aminoquinolone
• Urea
• Methionine-tRNA Ligase

Topics

• Administration, Oral
• Aminoquinolines (chemistry)
• Animals
• Biological Availability
• Brain (metabolism)
• Cell Line
• Cell Membrane Permeability
• Enzyme Inhibitors (chemistry, metabolism, pharmacokinetics, pharmacology)
• Female
• Humans
• Methionine-tRNA Ligase (antagonists & inhibitors, chemistry, metabolism)
• Mice
• Models, Molecular
• Protein Conformation
• Substrate Specificity
• Trypanosoma brucei brucei (enzymology)
• Urea (chemistry, metabolism, pharmacokinetics, pharmacology)