Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A 4 Hydrolase

• Published in: Journal of medicinal chemistry 2021-02, Vol.64 (4), p.1889-1903
• Main Authors: Markert, Christian, Thoma, Gebhard, Srinivas, Honnappa, Bollbuck, Birgit, Lüönd, Rainer M, Miltz, Wolfgang, Wälchli, Rudolf, Wolf, Romain, Hinrichs, Jürgen, Bergsdorf, Christian, Azzaoui, Kamal, Penno, Carlos A, Klein, Kai, Wack, Nathalie, Jäger, Petra, Hasler, Franziska, Beerli, Christian, Loetscher, Pius, Dawson, Janet, Wieczorek, Grazyna, Numao, Shin, Littlewood-Evans, Amanda, Röhn, Till A
• Format: Article
• Language: English
• Subjects: Aminobutyrates - chemical synthesis; Aminobutyrates - pharmacokinetics; Aminobutyrates - therapeutic use; Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - pharmacokinetics; Anti-Inflammatory Agents - pharmacology; Arthritis, Experimental - drug therapy; Dogs; Drug Discovery; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - therapeutic use; Epoxide Hydrolases - antagonists & inhibitors; Female; Humans; Inflammation - drug therapy; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Pyridines - chemical synthesis; Pyridines - pharmacokinetics; Pyridines - therapeutic use; Rats; Rats, Wistar; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01955

The cytosolic metalloenzyme leukotriene A hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B (LTB ). 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 LTB generation at low exposures , 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.