(S)-BI 665915

(S)-BI 665915 is an orally active oxadiazole-containing 5-lipoxygenase-activating protein (FLAP) inhibitor with an IC50 of 1.7 nM for FLAP binding. (S)-BI 665915 inhibits FLAP functional in human whole blood with an IC50 of 45 nM. (S)-BI 665915 demonstrates an excellent cross-species drug metabolism and pharmacokinetics (DMPK) profile and a dose-dependent inhibition of LTB4 production[1].

Signaling Pathways >> Immunology/Inflammation >> FLAP

Research Areas >> Inflammation/Immunology

IC50: 1.7 nM (FLAP) and 45 nM (FLAP functional in human whole blood)[1]

(S)-BI 665915 shows significantly weaker activity in mouse whole blood (mWB) assay than in human whole blood (mWB IC50=4800 nM; hWB IC50=45 nM)[1]. (S)-BI 665915 shows a modest human hepatocyte clearance (41% percent of hepatic blood flow) and relatively high plasma protein binding (unbound fraction of 4.7%)[1].

(S)-BI 665915 (oral; 1-100 mg/kg) demonstrates dose-dependent LTB4 production inhibition in mouse whole blood, 2 h after single oral dose[1]. (S)-BI 665915 (iv of 1 mg/kg or po of 10 mg/kg) shows low iv plasma clearance in all three species, with clearance values of 7 % Qh in rat, 2.8 % Qh in dog, and 3.6 % Qh in cynomolgus monkey, respectively. The volume of distribution (Vss) across species tested is in a range of 0.5 to 1.2 L/kg, and the bioavailability was good (45 to 63 %) in all species tested[1]. Animal Model: C57BL/6 mice[1] Dosage: 1, 3, 10, 30, 100 mg/kg (Pharmacokinetic Analysis) Administration: Oral Result: Demonstrated dose-dependent LTB4 production inhibition in mouse whole blood, 2 h after single oral dose. Animal Model: Rat; dog; cynomolgus monkey[1] Dosage: 1 mg/kg (iv) or 10 mg/kg (po) Administration: Iv or po Result: Showed low iv plasma clearance in all three species, with clearance values of 7 % Qh in rat, 2.8 % Qh in dog, and 3.6 % Qh in cynomolgus monkey, respectively.

[1]. Takahashi H, et al. Synthesis, SAR, and series evolution of novel oxadiazole-containing 5-lipoxygenase activating protein inhibitors: discovery of 2-[4-(3-{(r)-1-[4-(2-amino-pyrimidin-5-yl)-phenyl]-1-cyclopropyl-ethyl}-[1,2,4]oxadiazol-5-yl)-pyrazol-1-yl]-N,N-dimethyl-acetamide (BI 665915). J Med Chem. 2015 Feb 26;58(4):1669-90.