53657-72-0Relevant academic research and scientific papers
Potent and selective inhibitors of human reticulocyte 12/15-lipoxygenase as anti-stroke therapies
Rai, Ganesha,Joshi, Netra,Jung, Joo Eun,Liu, Yu,Schultz, Lena,Yasgar, Adam,Perry, Steve,Diaz, Giovanni,Zhang, Qiangli,Kenyon, Victor,Jadhav, Ajit,Simeonov, Anton,Lo, Eng H.,Van Leyen, Klaus,Maloney, David J.,Holman, Theodore R.
supporting information, p. 4035 - 4048 (2014/06/09)
A key challenge facing drug discovery today is variability of the drug target between species, such as with 12/15-lipoxygenase (12/15-LOX), which contributes to ischemic brain injury, but its human and rodent isozymes have different inhibitor specificities. In the current work, we have utilized a quantitative high-throughput (qHTS) screen to identify compound 1 (ML351), a novel chemotype for 12/15-LOX inhibition that has nanomolar potency (IC 50 = 200 nM) against human 12/15-LOX and is protective against oxidative glutamate toxicity in mouse neuronal HT22 cells. In addition, it exhibited greater than 250-fold selectivity versus related LOX isozymes, was a mixed inhibitor, and did not reduce the active-site ferric ion. Lastly, 1 significantly reduced infarct size following permanent focal ischemia in a mouse model of ischemic stroke. As such, this represents the first report of a selective inhibitor of human 12/15-LOX with demonstrated in vivo activity in proof-of-concept mouse models of stroke.
Evolution of the thienopyridine class of inhibitors of IκB kinase-β: Part I: Hit-to-lead strategies
Morwick, Tina,Berry, Angela,Brickwood, Janice,Cardozo, Mario,Catron, Katrina,DeTuri, Molly,Emeigh, Jonathan,Homon, Carol,Hrapchak, Matt,Jacober, Stephen,Jakes, Scott,Kaplita, Paul,Kelly, Terence A.,Ksiazek, John,Liuzzi, Michel,Magolda, Ronald,Mao, Can,Marshall, Daniel,McNeil, Daniel,Prokopowicz II, Anthony,Sarko, Christopher,Scouten, Erika,Sledziona, Cynthia,Sun, Sanxing,Watrous, Jane,Wu, Jiang Ping,Cywin, Charles L.
, p. 2898 - 2908 (2007/10/03)
High-throughput screening is routinely employed as a method for the identification of novel hit structures. Large numbers of active compounds are typically procured in this way and must undergo a rigorous validation process. This process is described in detail for a collection of screening hits identified as inhibitors of IκB kinase-β (IKKβ), a key regulatory enzyme in the nuclear factor-κB (NF-κB) pathway. From these studies, a promising hit series was selected. Subsequent lead generation activities included the development of a pharmacophore hypothesis and structure-activity relationship (SAR) for the hit series. This led to the exploration of related scaffolds offering additional opportunities, and the various structural classes were comparatively evaluated for enzyme inhibition, selectivity, and drug-like properties. A novel lead series of thienopyridines was thereby established, and this series advanced into lead optimization for further development.
