57928-64-0Relevant academic research and scientific papers
Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A4Hydrolase
Markert, Christian,Thoma, Gebhard,Srinivas, Honnappa,Bollbuck, Birgit,Lü?nd, Rainer M.,Miltz, Wolfgang,W?lchli, Rudolf,Wolf, Romain,Hinrichs, Jürgen,Bergsdorf, Christian,Azzaoui, Kamal,Penno, Carlos A.,Klein, Kai,Wack, Nathalie,J?ger, Petra,Hasler, Franziska,Beerli, Christian,Loetscher, Pius,Dawson, Janet,Wieczorek, Grazyna,Numao, Shin,Littlewood-Evans, Amanda,R?hn, Till A.
supporting information, p. 1889 - 1903 (2021/03/09)
The cytosolic metalloenzyme leukotriene A4 hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B4 (LTB4). Preclinical studies have validated this enzyme as an attractive drug target in chronic inflammatory diseases. Despite several attempts, no LTA4H inhibitor has reached the market, yet. Herein, we disclose the discovery and preclinical profile of LYS006, a highly potent and selective LTA4H inhibitor. A focused fragment screen identified hits that could be cocrystallized with LTA4H and inspired a fragment merging. Further optimization led to chiral amino acids and ultimately to LYS006, a picomolar LTA4H inhibitor with exquisite whole blood potency and long-lasting pharmacodynamic effects. Due to its high selectivity and its ability to fully suppress LTB4 generation at low exposures in vivo, LYS006 has the potential for a best-in-class LTA4H inhibitor and is currently investigated in phase II clinical trials in inflammatory acne, hidradenitis suppurativa, ulcerative colitis, and NASH.
N-Heterocyclic carbene-mediated redox condensation of alcohols
Kato, Terumasa,Matsuoka, Shin-Ichi,Suzuki, Masato
supporting information, p. 8569 - 8572 (2016/07/13)
N-Heterocyclic carbenes (NHCs) with a variety of oxidants promote the Mitsunobu-type coupling reactions of alcohols with phenols, carboxylic acids, and phthalimide. Experiments using a chiral alcohol indicate that these reactions proceed via SN1 or SN2 pathways depending on the polarity of the used solvents. The NHCs are consumed as reducing reagents to form their oxides as readily separable byproducts.
