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 the artcile< Discovery of Potent and Orally Bioavailable Pyridine N-Oxide-Based Factor XIa Inhibitors through Exploiting Nonclassical Interactions>, Formula: C4H5BrN2, the main research area is cyclopropylpyrazolyl pyridine oxide preparation anticoagulation docking SAR.
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.
Journal of Medicinal Chemistry published new progress about Anticoagulants, oral. 1003-21-0 belongs to class imidazoles-derivatives, and the molecular formula is C4H5BrN2, Formula: C4H5BrN2.
Referemce:
Imidazole – Wikipedia,
Imidazole | C3H4N2 – PubChem