29051-45-4Relevant academic research and scientific papers
Fragment growing and linking lead to novel nanomolar lactate dehydrogenase inhibitors
Kohlmann, Anna,Zech, Stephan G.,Li, Feng,Zhou, Tianjun,Squillace, Rachel M.,Commodore, Lois,Greenfield, Matthew T.,Lu, Xiaohui,Miller, David P.,Huang, Wei-Sheng,Qi, Jiwei,Thomas, R. Mathew,Wang, Yihan,Zhang, Sen,Dodd, Rory,Liu, Shuangying,Xu, Rongsong,Xu, Yongjin,Miret, Juan J.,Rivera, Victor,Clackson, Tim,Shakespeare, William C.,Zhu, Xiaotian,Dalgarno, David C.
, p. 1023 - 1040 (2013/03/28)
Lactate dehydrogenase A (LDH-A) catalyzes the interconversion of lactate and pyruvate in the glycolysis pathway. Cancer cells rely heavily on glycolysis instead of oxidative phosphorylation to generate ATP, a phenomenon known as the Warburg effect. The inhibition of LDH-A by small molecules is therefore of interest for potential cancer treatments. We describe the identification and optimization of LDH-A inhibitors by fragment-based drug discovery. We applied ligand based NMR screening to identify low affinity fragments binding to LDH-A. The dissociation constants (Kd) and enzyme inhibition (IC 50) of fragment hits were measured by surface plasmon resonance (SPR) and enzyme assays, respectively. The binding modes of selected fragments were investigated by X-ray crystallography. Fragment growing and linking, followed by chemical optimization, resulted in nanomolar LDH-A inhibitors that demonstrated stoichiometric binding to LDH-A. Selected molecules inhibited lactate production in cells, suggesting target-specific inhibition in cancer cell lines.
Design and synthesis of 6-phenylnicotinamide derivatives as antagonists of TRPV1
Westaway, Susan M.,Thompson, Mervyn,Rami, Harshad K.,Stemp, Geoffrey,Trouw, Leontine S.,Mitchell, Darren J.,Seal, Jon T.,Medhurst, Stephen J.,Lappin, Sarah C.,Biggs, James,Wright, James,Arpino, Sandra,Jerman, Jeffrey C.,Cryan, Jennifer E.,Holland, Vicky,Winborn, Kim Y.,Coleman, Tanya,Stevens, Alexander J.,Davis, John B.,Gunthorpe, Martin J.
scheme or table, p. 5609 - 5613 (2009/06/18)
6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development.
