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)

• Published in: Journal of medicinal chemistry Vol. 58; no. 4; pp. 1669 - 1690
• Main Authors: Takahashi, Hidenori, Riether, Doris, Bartolozzi, Alessandra, Bosanac, Todd, Berger, Valentina, Binetti, Ralph, Broadwater, John, Chen, Zhidong, Crux, Rebecca, De Lombaert, Stéphane, Dave, Rajvee, Dines, Jonathon A, Fadra-Khan, Tazmeen, Flegg, Adam, Garrigou, Michael, Hao, Ming-Hong, Huber, John, Hutzler, J. Matthew, Kerr, Steven, Kotey, Adrian, Liu, Weimin, Lo, Ho Yin, Loke, Pui Leng, Mahaney, Paige E, Morwick, Tina M, Napier, Spencer, Olague, Alan, Pack, Edward, Padyana, Anil K, Thomson, David S, Tye, Heather, Wu, Lifen, Zindell, Renee M, Abeywardane, Asitha, Simpson, Thomas
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.02.2015; Amer Chemical Soc
• Subjects: Acetamides - chemical synthesis; Acetamides - chemistry; Acetamides - pharmacology; Arachidonate 5-Lipoxygenase - metabolism; Chemistry, Medicinal; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Discovery; Humans; Life Sciences & Biomedicine; Lipoxygenase Inhibitors - chemical synthesis; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; Models, Molecular; Molecular Conformation; Oxadiazoles - chemical synthesis; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; INFLAMMATORY DISEASES; FLAP; INDUCED AIRWAY RESPONSES; CARDIOVASCULAR-DISEASE; ATHEROSCLEROSIS; RANDOMIZED-TRIAL; LEUKOTRIENE BIOSYNTHESIS INHIBITOR; DOUBLE KNOCKOUT MICE; ASTHMATIC SUBJECTS; MEDIATORS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm501185j

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.