In 2022,Xu, Guozhang; Liu, Zhijie; Wang, Xinkang; Lu, Tianbao; DesJarlais, Renee L.; Thieu, Tho; Zhang, Jing; Devine, Zheng Huang; Du, Fuyong; Li, Qiu; Milligan, Cynthia M.; Shaffer, Paul; Cedervall, Peder E.; Spurlino, John C.; Stratton, Christopher F.; Pietrak, Beth; Szewczuk, Lawrence M.; Wong, Victoria; Steele, Ruth A.; Bruinzeel, Wouter; Chintala, Madhu; Silva, Jose; Gaul, Michael D.; Macielag, Mark J.; Nargund, Ravi published an article in Journal of Medicinal Chemistry. The title of the article was 《Discovery of Potent and Orally Bioavailable Pyridine N-Oxide-Based Factor XIa Inhibitors through Exploiting Nonclassical Interactions》.Reference of 2,5-Dibromopyridine The author mentioned the following in the article:
Herein, activated factor XI (FXIa) inhibitors novel anticoagulants, discovery effort, utilizing nonclassical interactions to improve potency, cellular permeability, and oral bioavailability by enhancing the binding while reducing polar atoms was described. Beginning with literature-inspired pyridine N-oxide-based FXIa inhibitor 1, the imidazole linker was first replaced with a pyrazole moiety to establish a polar C-H···water hydrogen-bonding interaction. Then, structure-based drug design was employed to modify lead mol. I in the P1′ and P2′ regions, with substituents interacting with key residues through various nonclassical interactions. As a result, a potent FXIa inhibitor II (Ki = 0.17 nM) was discovered. This compound demonstrated oral bioavailability in preclin. species (rat 36.4%, dog 80.5%, and monkey 43.0%) and displayed a dose-dependent antithrombotic effect in a rabbit arteriovenous shunt model of thrombosis.2,5-Dibromopyridine(cas: 624-28-2Reference of 2,5-Dibromopyridine) was used in this study.
2,5-Dibromopyridine(cas: 624-28-2) belongs to pyridine. Pyridine is very deactivated towards electrophilic substitution with respect to benzene. For this reason classical formylation, using methods such as the Gattermann or Vilsmeier reactions, are not generally successful. Reference of 2,5-Dibromopyridine