Discovery and Early Clinical Development of an Inhibitor of 5‑Lipoxygenase Activating Protein (AZD5718) for Treatment of Coronary Artery Disease

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.