4Y8Z

Factor XIa in complex with the inhibitor (2E)-N-[(1S)-1-[5-chloro-4-(4-hydroxy-2-oxo-1,2-dihydroquinolin-6-yl)-1H-imidazol-2-yl]-3-(4-methylpiperazin-1-yl)-3-oxopropyl]-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enamide

Summary for 4Y8Z

• Entry DOI: 10.2210/pdb4y8z/pdb
• Related: 4Y8X 4Y8Y
• Descriptor: Coagulation factor XIa, (2E)-N-[(1S)-1-[5-chloro-4-(4-hydroxy-2-oxo-1,2-dihydroquinolin-6-yl)-1H-imidazol-2-yl]-3-(4-methylpiperazin-1-yl)-3-oxopropyl]-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enamide, 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: 28670.26

Authors

Sheriff, S. (deposition date: 2015-02-16, release date: 2015-05-27, Last modification date: 2024-10-30)

Primary citation

Hu, Z.,Wong, P.C.,Gilligan, P.J.,Han, W.,Pabbisetty, K.B.,Bozarth, J.M.,Crain, E.J.,Harper, T.,Luettgen, J.M.,Myers, J.E.,Ramamurthy, V.,Rossi, K.A.,Sheriff, S.,Watson, C.A.,Wei, A.,Zheng, J.J.,Seiffert, D.A.,Wexler, R.R.,Quan, M.L.
Discovery of a Potent Parenterally Administered Factor XIa Inhibitor with Hydroxyquinolin-2(1H)-one as the P2' Moiety.
ACS Med Chem Lett, 6:590-595, 2015

PubMed Abstract: Structure-activity relationship optimization of phenylalanine P1' and P2' regions with a phenylimidazole core resulted in a series of potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one as the P2' group enhanced FXIa affinity and metabolic stability. Incorporation of an N-methyl piperazine amide group to replace the phenylalanine improved both FXIa potency and aqueous solubility. Combination of the optimization led to the discovery of FXIa inhibitor 13 with a FXIa K i of 0.04 nM and an aPTT EC2x of 1.0 μM. Dose-dependent efficacy (EC50 of 0.53 μM) was achieved in the rabbit ECAT model with minimal bleeding time prolongation.

PubMed: 26005539
DOI: 10.1021/acsmedchemlett.5b00066

Experimental method

X-RAY DIFFRACTION (2.2 Å)