5TKT

FACTOR XIA IN COMPLEX WITH THE INHIBITOR METHYL ((12E,15S)-15-(((2E)-3-(5-CHLORO-2-(1H-TETRAZOL-1-YL)PHENYL)-2-PROPENOYL)AMINO)-9-OXO-8,17,19-TRIAZATRICYCLO[14.2.1.0~2,7~]NONADECA-1(18),2,4,6,12,16(19)-HEXAEN-5-YL)CARBAMATE

Summary for 5TKT

• Entry DOI: 10.2210/pdb5tkt/pdb
• Related: 5TKS 5TKU
• Descriptor: Factor XIa (Light Chain), METHYL ((12E,15S)-15-(((2E)-3-(5-CHLORO-2-(1H-TETRAZOL-1-YL)PHENYL)-2-PROPENOYL)AMINO)-9-OXO-8,17,19-TRIAZATRICYCLO[14.2.1.0~2, 7~]NONADECA-1(18),2,4,6,12,16(19)-HEXAEN-5-YL)CARBAMATE, SULFATE ION, ... (5 entities in total)
• Functional Keywords: hydrolase, serine protease, blood coagulation factor, protein inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted: P03951
• Total number of polymer chains: 1
• Total formula weight: 29063.23

Authors

Sheriff, S. (deposition date: 2016-10-07, release date: 2017-03-01, Last modification date: 2024-10-23)

Primary citation

Corte, J.R.,Fang, T.,Osuna, H.,Pinto, D.J.,Rossi, K.A.,Myers, J.E.,Sheriff, S.,Lou, Z.,Zheng, J.J.,Harper, T.W.,Bozarth, J.M.,Wu, Y.,Luettgen, J.M.,Seiffert, D.A.,Decicco, C.P.,Wexler, R.R.,Quan, M.L.
Structure-Based Design of Macrocyclic Factor XIa Inhibitors: Discovery of the Macrocyclic Amide Linker.
J. Med. Chem., 60:1060-1075, 2017

PubMed Abstract: A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery of a macrocyclic amide linker which was found to form a key hydrogen bond with the carbonyl of Leu41 in the FXIa active site, resulting in potent FXIa inhibitors. The macrocyclic FXIa series, exemplified by compound 16, had a FXIa K = 0.16 nM with potent anticoagulant activity in an in vitro clotting assay (aPTT EC = 0.27 μM) and excellent selectivity against the relevant blood coagulation enzymes.

PubMed: 28085275
DOI: 10.1021/acs.jmedchem.6b01460

Experimental method

X-RAY DIFFRACTION (2.12 Å)