Discovery and Early Clinical Development of an Inhibitor of 5-Lipoxygenase Activating Protein (AZD5718) for Treatment of Coronary Artery Disease
| Autor: | Hans Ericsson, Igor L. Shamovsky, Carl Whatling, Malin Lemurell, Marianne Swanson, Eva-Lotte Lindstedt, Johan Broddefalk, Mats Någård, Anita Dellsén, Johan Ulander, Carl Amilon, Kenneth Granberg, Annika Westin Eriksson, Daniel Pettersen, Alleyn T. Plowright, Monica Sundqvist, Hans Emtenäs, Martin A. Hayes |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
Leukotriene Production Inflammation Coronary Artery Disease Pharmacology Leukotriene B4 01 natural sciences Proinflammatory cytokine Rats Sprague-Dawley Coronary artery disease Structure-Activity Relationship 03 medical and health sciences Dogs Cell Line Tumor Drug Discovery medicine Animals Humans 5-lipoxygenase-activating protein 030304 developmental biology Whole blood 0303 health sciences Clinical Trials Phase I as Topic Molecular Structure biology Drug discovery Chemistry medicine.disease 0104 chemical sciences Clinical trial 010404 medicinal & biomolecular chemistry 5-Lipoxygenase-Activating Protein Inhibitors biology.protein Pyrazoles Molecular Medicine Female medicine.symptom |
| Zdroj: | Journal of Medicinal Chemistry. 62:4312-4324 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.8b02004 |
| Popis: | 5-Lipoxygenase activating protein (FLAP) inhibitors attenuate 5-lipoxygenase pathway activity and reduce the production of proinflammatory and vasoactive leukotrienes. As such, they are hypothesized to have therapeutic benefit for the treatment of diseases that involve chronic inflammation including coronary artery disease. Herein, we disclose the medicinal chemistry discovery and the early clinical development of the FLAP inhibitor AZD5718 (12). Multiparameter optimization included securing adequate potency in human whole blood, navigation away from Ames mutagenic amine fragments while balancing metabolic stability and PK properties allowing for clinically relevant exposures after oral dosing. The superior safety profile of AZD5718 compared to earlier frontrunner compounds allowed us to perform a phase 1 clinical study in which AZD5718 demonstrated a dose dependent and greater than 90% suppression of leukotriene production over 24 h. Currently, AZD5718 is evaluated in a phase 2a study for treatment of coronary artery disease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|