Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A4 Hydrolase
| العنوان: | Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A4 Hydrolase |
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| المؤلفون: | Christian Markert, Shin Numao, Petra Jäger, Gebhard Thoma, Rudolf Wälchli, Grazyna Wieczorek, Nathalie Wack, Franziska Hasler, Jürgen Hinrichs, Rainer M. Lüönd, Christian Beerli, Honnappa Srinivas, Amanda Littlewood-Evans, Pius Loetscher, Kai Klein, Carlos A. Penno, Kamal Azzaoui, Romain M. Wolf, Birgit Bollbuck, Till A. Röhn, Christian Bergsdorf, Wolfgang Miltz, Janet Dawson |
| المصدر: | Journal of Medicinal Chemistry. 64:1889-1903 |
| بيانات النشر: | American Chemical Society (ACS), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | chemistry.chemical_classification, Drug discovery, Leukotriene B4, Pharmacology, Amino acid, Leukotriene-A4 hydrolase, chemistry.chemical_compound, Enzyme, chemistry, Biosynthesis, In vivo, Drug Discovery, Molecular Medicine, Structure–activity relationship |
| الوصف: | 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. |
| تدمد: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c01955 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::208c74664f1cf048b5387b6f462e34b0 https://doi.org/10.1021/acs.jmedchem.0c01955 |
| Rights: | CLOSED |
| رقم الانضمام: | edsair.doi...........208c74664f1cf048b5387b6f462e34b0 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15204804 00222623 |
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| DOI: | 10.1021/acs.jmedchem.0c01955 |