Document Detail

Design, synthesis, and pharmacological evaluation of bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES) analogs as glutaminase inhibitors.
MedLine Citation:
PMID:  23151085     Owner:  NLM     Status:  MEDLINE    
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.
Krupa Shukla; Dana V Ferraris; Ajit G Thomas; Marigo Stathis; Bridget Duvall; Greg Delahanty; Jesse Alt; Rana Rais; Camilo Rojas; Ping Gao; Yan Xiang; Chi V Dang; Barbara S Slusher; Takashi Tsukamoto
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-30
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  55     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-13     Completed Date:  2013-02-26     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  10551-63     Citation Subset:  IM    
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MeSH Terms
Drug Design*
Enzyme Inhibitors / chemical synthesis,  chemistry*,  pharmacology*
Glutaminase / antagonists & inhibitors*
Magnetic Resonance Spectroscopy
Models, Molecular
Sulfides / chemical synthesis,  chemistry*,  pharmacology*
Thiadiazoles / chemical synthesis,  chemistry*,  pharmacology*
Grant Support
1R21NS074151-01/NS/NINDS NIH HHS; 2P30MH075673-06/MH/NIMH NIH HHS; P30 CA016520/CA/NCI NIH HHS; R01 CA057341/CA/NCI NIH HHS; R01CA051497-22/CA/NCI NIH HHS; R03DA032470-01A1/DA/NIDA NIH HHS; R21 NS074151/NS/NINDS NIH HHS
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Sulfides; 0/Thiadiazoles; 0/bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; EC

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