Synthesis, SAR, and Series Evolution of Novel Oxadiazole-Containing 5‑Lipoxygenase Activating Protein Inhibitors: Discovery of 2‑[4-(3-{(<i>R</i>)‑1-[4-(2-Amino-pyrimidin-5-yl)-phenyl]-1-cyclopropyl-ethyl}-[1,2,4]oxadiazol-5-yl)-pyrazol-1-yl]‑<i>N</i>,<i>N</i>‑dimethyl-acetamide (BI 665915)

The synthesis, structure–activity relationship (SAR), and evolution of a novel series of oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitors are described. The use of structure-guided drug design techniques provided compounds that demonstrated excellent FLAP binding potency (IC₅₀ < 10 nM) and potent inhibition of LTB₄ synthesis in human whole blood (IC₅₀ < 100 nM). Optimization of binding and functional potencies, as well as physicochemical properties resulted in the identification of compound <b>69</b> (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, <b>69</b> was predicted to have a low risk for potential drug–drug interactions due to its cytochrome P450 3A4 profile. In a murine <i>ex vivo</i> whole blood study, <b>69</b> demonstrated a linear dose–exposure relationship and a dose-dependent inhibition of LTB₄ production