Design, synthesis, and pharmacological evaluation of bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) analogs as glutaminase inhibitors

J Med Chem. 2012 Dec 13;55(23):10551-63. doi: 10.1021/jm301191p. Epub 2012 Nov 30.


Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) is a potent and selective allosteric inhibitor of kidney-type glutaminase (GLS) that has served as a molecular probe to determine the therapeutic potential of GLS inhibition. In an attempt to identify more potent GLS inhibitors with improved drug-like molecular properties, a series of BPTES analogs were synthesized and evaluated. Our structure-activity relationship (SAR) studies revealed that some truncated analogs retained the potency of BPTES, presenting an opportunity to improve its aqueous solubility. One of the analogs, N-(5-{2-[2-(5-amino-[1,3,4]thiadiazol-2-yl)-ethylsulfanyl]-ethyl}-[1,3,4]thiadiazol-2-yl)-2-phenyl-acetamide 6, exhibited similar potency and better solubility relative to BPTES and attenuated the growth of P493 human lymphoma B cells in vitro as well as in a mouse xenograft model.

Publication types

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

MeSH terms

  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Glutaminase / antagonists & inhibitors*
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Sulfides / chemical synthesis
  • Sulfides / chemistry*
  • Sulfides / pharmacology*
  • Thiadiazoles / chemical synthesis
  • Thiadiazoles / chemistry*
  • Thiadiazoles / pharmacology*


  • Enzyme Inhibitors
  • Sulfides
  • Thiadiazoles
  • bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide
  • Glutaminase