Novel Chemical Series of 5‑Lipoxygenase-Activating Protein Inhibitors for Treatment of Coronary Artery Disease

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.