5-Lipoxygenase-activating protein (FLAP) is essential for cellular leukotriene synthesis. FLAP is the target of leukotriene biosynthesis inhibitors. The 5-lipoxygenase pathway is responsible for the production of leukotrienes, lipid mediators derived from arachidonic acid that have inflammatory and vasoactive actions and that are involved in the innate immune response. Biological actions of leukotrienes include stimulation of leukocyte chemotaxis, neutrophil activation, promotion of vasopermeability, and vasoconstriction. FLAP inhibitors attenuate 5-lipoxygenase pathway activity and reduce the production of proinflammatory and vasoactive leukotrienes.

In this study, researchers disclose the medicinal chemistry discovery and the early clinical development of the FLAP inhibitor AZD5718. In particular, AZD5718 is an inhibitor of 5-lipoxygenase activating protein for the treatment of coronary artery disease. AZD5718 demonstrates a dose-dependent and greater than 90% suppression of leukotriene production over 24 h. The LTB4 IC50 value for AZD5718 is 39 nM, and the IC80 value is 116 nM in the human whole blood assay. AZD5718 also shows excellent potency in inhibiting LTB4 production in the human whole blood assay (IC50=2.0 nM). AZD5718 demonstrates inhibition of hBSEP and hMrp2 transport proteins.

In vivo, AZD5718 rapidly absorbed and maximum plasma concentration (Cmax) generally reached within 1–2 h following administration. Moreover, AZD5718 displays a promising profile from metabolic stability and Caco-2 permeability perspective. Furthermore, AZD5718 is well tolerated, and no adverse clinical signs.

Overall, AZD5718 is an orally active FLAP inhibitor. FLAP plays a critical role in the metabolism of arachidonic acid to leukotriene A4, the precursor to the potent pro-inflammatory mediators leukotriene B4 and leukotriene C4.

Daniel Pettersen, et al. Discovery and Early Clinical Development of an Inhibitor of 5-Lipoxygenase Activating Protein (AZD5718) for Treatment of Coronary Artery Disease. J Med Chem. 2019 May 9;62(9):4312-4324.