Novel Chemical Series of 5-Lipoxygenase-Activating Protein Inhibitors for Treatment of Coronary Artery Disease
| Autor: | Christian Löfberg, Marianne Swanson, ZhongQing Yuan, Johan Broddefalk, Annika Westin Eriksson, Susanne Winiwarter, Martin A. Hayes, Gabrielle Saarinen, Johan Meuller, Carl Whatling, Johan Ulander, Hans Emtenäs, Johan Cassel, Monica Sundqvist, Malin Lemurell, Luna Prieto Garcia, Staffan Karlsson |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Leukotriene B4 Leukotriene Production 5-Lipoxygenase-Activating Protein Inhibitors Coronary Artery Disease Pharmacology 01 natural sciences Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Dogs In vivo Cyclohexanes Drug Discovery Structure–activity relationship Animals Humans 030304 developmental biology 0303 health sciences Ligand efficiency Molecular Structure Chemistry In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry Molecular Medicine Pyrazoles Female Caco-2 Cells Ex vivo |
| Zdroj: | Journal of medicinal chemistry. 62(9) |
| ISSN: | 1520-4804 |
| Popis: | 5-Lipoxygenase (5-LO)-activating protein (FLAP) inhibitors have proven to attenuate 5-LO pathway activity and leukotriene production in human clinical trials. However, previous clinical candidates have been discontinued and the link between FLAP inhibition and outcome in inflammatory diseases remains to be established. We here describe a novel series of FLAP inhibitors identified from a screen of 10k compounds and the medicinal chemistry strategies undertaken to progress this series. Compound 4i showed good overall properties and a pIC50 hWBfree of 8.1 and an lipophilic ligand efficiency of 5.2. Target engagement for 4i was established in dogs using ex vivo measurement of leukotriene B4 (LTB4) levels in blood with good correlation to in vitro potency. A predicted human dose of 280 mg b.i.d. suggests a wide margin to any identified in vitro off-target effects and sufficient exposure to achieve an 80% reduction of LTB4 levels in humans. Compound 4i is progressed to preclinical in vivo safety studies. |
| Databáze: | OpenAIRE |
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