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)
2015; American Chemical Society; Volume: 58; Issue: 4 Linguagem: Inglês
10.1021/jm501185j
ISSN1520-4804
AutoresHidenori Takahashi, Doris Riether, Alessandra Bartolozzi, Todd Bosanac, Valentina Berger, Ralph Binetti, John A. Broadwater, Zhidong Chen, Rebecca Crux, Stéphane De Lombaert, Rajvee Dave, Jonathon A. Dines, Tazmeen Fadra-Khan, Adam Flegg, Michael Garrigou, Ming‐Hong Hao, John D. Huber, J. Matthew Hutzler, Steven Kerr, Adrian Kotey, Weimin Liu, Ho Yin Lo, Pui L. Loke, Paige E. Mahaney, Tina M. Morwick, Spencer Napier, Alan Olague, Edward J. Pack, Anil K. Padyana, David Thomson, Heather Tye, Lifen Wu, Renée Zindell, Asitha Abeywardane, Thomas Simpson,
Tópico(s)Quinazolinone synthesis and applications
ResumoThe 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.
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