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Although some of the inhibitors show efficacy in different animal models, which implies potential for therapeutic use in human, there is not yet a chemical entity reported in clinical trials. The prospects for Itk inhibitors will rely on the quality of the compound and the validity of the target in patients within the selected therapeutic area.

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 69 (BI 665915) that demonstrated an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and was predicted to have low human clearance. In addition, 69 was predicted to have a low risk for potential drug-drug interactions due to its cytochrome P450 3A4 profile. In a murine ex vivo whole blood study, 69 demonstrated a linear dose-exposure relationship and a dose-dependent inhibition of LTB4 production.

Examples are provided of stereospecific transannular oxidation-reduction processes involving the conjugate bases of delta-hydroxy ketones in a nine-membered ring setting. The ability to control the direction of these equilibria by proper modulation of the solvent environment and level of hydroxyl group protection is demonstrated. MM3-derived steric energies of the isomer pairs suggest that the equilibrium distributions are the outcome of the extent to which intramolecular hydrogen bonding forces are disrupted by polar solvent molecules when present.

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