Urea-based inhibitors of Trypanosoma brucei methionyl-tRNA synthetase: selectivity and in vivo characterization.
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.
Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Sayaka
S
Shibata
J Robert
JR
Gillespie
Ranae M
RM
Ranade
Cho Yeow
CY
Koh
Jessica E
JE
Kim
Joy U
JU
Laydbak
Frank H
FH
Zucker
Wim G J
WG
Hol
Christophe L M J
CL
Verlinde
Frederick S
FS
Buckner
Erkang
E
Fan
D000284:Administration, Oral; D000634:Aminoquinolines / Q000737:chemistry; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002463:Cell Membrane Permeability; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008718:Methionine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D013379:Substrate Specificity; D014346:Trypanosoma brucei brucei / Q000201:enzymology*; D014508:Urea / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*
D000634:Aminoquinolines; D004791:Enzyme Inhibitors; C025152:aminoquinolone; D014508:Urea; D008718:Methionine-tRNA Ligase