219986-58-0Relevant academic research and scientific papers
Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH)
Rai, Ganesha,Brimacombe, Kyle R.,Mott, Bryan T.,Urban, Daniel J.,Hu, Xin,Yang, Shyh-Ming,Lee, Tobie D.,Cheff, Dorian M.,Kouznetsova, Jennifer,Benavides, Gloria A.,Pohida, Katie,Kuenstner, Eric J.,Luci, Diane K.,Lukacs, Christine M.,Davies, Douglas R.,Dranow, David M.,Zhu, Hu,Sulikowski, Gary,Moore, William J.,Stott, Gordon M.,Flint, Andrew J.,Hall, Matthew D.,Darley-Usmar, Victor M.,Neckers, Leonard M.,Dang, Chi V.,Waterson, Alex G.,Simeonov, Anton,Jadhav, Ajit,Maloney, David J.
supporting information, p. 9184 - 9204 (2017/12/05)
We report the discovery and medicinal chemistry optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compounds with potent enzymatic and cell-based inhibition of LDH enzymatic activity. Lead compounds such as 63 exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate production, and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells. Moreover, robust target engagement of LDHA by lead compounds was demonstrated using the cellular thermal shift assay (CETSA), and drug-target residence time was determined via SPR. Analysis of these data suggests that drug-target residence time (off-rate) may be an important attribute to consider for obtaining potent cell-based inhibition of this cancer metabolism target.
Synthesis and antibacterial activity of some 5-hydroxy-5-trifluoromethyl-4, 5-dihydropyrazol-1-thiocarboxamides, 3-trifluoromethylpyrazol-1-thiocarboxamides and 4-aryl-2-(5(3)-trifluoromethyl-1-pyrazolyl)thiazoles
Aggarwal, Ranjana,Kumar, Rajiv,Kumar, Sunil,Garg, Gaurav,Mahajan, Ritu,Sharma, Jitender
experimental part, p. 965 - 972 (2011/11/06)
5-Hydroxy-5-trifluoromethyl-4,5-dihydropyrazol-1-thiocarboxamides 3 and 3-trifluoromethylpyrazol-1-thiocarboxamides 4, regioselectively obtained by the condensation of trifluoromethyl-β-diketones with thiosemicarbazide under neutral and acidic conditions,
Haloacetylated enol ethers 10. Condensation of β-alkoxyvinyl trifluoromethyl ketones with thiosemicarbazide. Synthesis of new trifluoromethyl 4,5-dihydro-1H-1-pyrazolethiocarboxyamides
Bonacorso,Wastowski,Zanatta,Martins,Naue
, p. 23 - 26 (2007/10/03)
The synthesis of 3-aryl[alkyl]-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1- pyrazolethiocarboxyamides (2a-g) from the direct cyclo-condensation reaction of β-alkoxyvinyl trifluoromethyl ketones (1a-g) with thiosemicarbazide in methanol, under mild conditions, is reported. Similarly, the 1H-1-pyrazolethiocarboxyamide derivatives (2a-g) were easily dehydrated and the thiocarboxyamide group hydrolyzed in a one-step reaction by stirring with concentrated sulfuric acid to give the 3-aryl[alkyl]-5-trifluoromethyl-1H-pyrazoles (3a-g) in good yields. Specific syntheses and physical properties of 3-aryl[alkyl]-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1- pyrazolethiocarboxyamides are reported here for the first time.
