7V16
Factor XIa in Complex with Compound 2j
Summary for 7V16
| Entry DOI | 10.2210/pdb7v16/pdb |
| Descriptor | Coagulation factor XIa light chain, CITRIC ACID, 5-[3-chloranyl-2-fluoranyl-6-(1,2,3,4-tetrazol-1-yl)phenyl]-2-[(1~{R})-2-cyclopropyl-1-[4-(2-methylpyrazol-3-yl)pyrazol-1-yl]ethyl]-1-oxidanyl-pyridine, ... (4 entities in total) |
| Functional Keywords | hydrolase, serine protease, coagulation factor, blood clotting |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 27554.56 |
| Authors | Shaffer, P.L.,Milligan, C.M. (deposition date: 2022-05-11, release date: 2022-08-03, Last modification date: 2023-10-18) |
| Primary citation | Xu, G.,Liu, Z.,Wang, X.,Lu, T.,DesJarlais, R.L.,Thieu, T.,Zhang, J.,Devine, Z.H.,Du, F.,Li, Q.,Milligan, C.M.,Shaffer, P.,Cedervall, P.E.,Spurlino, J.C.,Stratton, C.F.,Pietrak, B.,Szewczuk, L.M.,Wong, V.,Steele, R.A.,Bruinzeel, W.,Chintala, M.,Silva, J.,Gaul, M.D.,Macielag, M.J.,Nargund, R. Discovery of Potent and Orally Bioavailable Pyridine N-Oxide-Based Factor XIa Inhibitors through Exploiting Nonclassical Interactions. J.Med.Chem., 65:10419-10440, 2022 Cited by PubMed Abstract: Activated factor XI (FXIa) inhibitors are promising novel anticoagulants with low bleeding risk compared with current anticoagulants. The discovery of potent FXIa inhibitors with good oral bioavailability has been challenging. Herein, we describe our discovery effort, utilizing nonclassical interactions to improve potency, cellular permeability, and oral bioavailability by enhancing the binding while reducing polar atoms. Beginning with literature-inspired pyridine N-oxide-based FXIa inhibitor , 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 molecule in the P1' and P2' regions, with substituents interacting with key residues through various nonclassical interactions. As a result, a potent FXIa inhibitor ( = 0.17 nM) was discovered. This compound demonstrated oral bioavailability in preclinical 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. PubMed: 35862732DOI: 10.1021/acs.jmedchem.2c00442 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.505 Å) |
Structure validation
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