4TY7: Factor XIa in complex with the inhibitor (2S)-6-amino-N-{(1S)-1-[4-(3-amino-2H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl]-2-phenylethyl}-2-ethylhexanamide

Novel inhibitors of FXIa containing an (S)-2-phenyl-1-(4-phenyl-1H-imidazol-2-yl)ethanamine core have been optimized to provide compound 16b, a potent, reversible inhibitor of FXIa (Ki = 0.3 nM) having in vivo antithrombotic efficacy in the rabbit AV-shunt thrombosis model (ID50 = 0.6 mg/kg + 1 mg kg(-1) h(-1)). Initial analog selection was informed by molecular modeling using compounds 11a and 11h overlaid onto the X-ray crystal structure of tetrahydroquinoline 3 complexed to FXIa. Further optimization was achieved by specific modifications derived from careful analysis of the X-ray crystal structure of the FXIa/11h complex. Compound 16b was well tolerated and enabled extensive pharmacologic evaluation of the FXIa mechanism up to the ID90 for thrombus inhibition.
PDB ID: 4TY7Download
MMDB ID: 125256
PDB Deposition Date: 2014/7/8
Updated in MMDB: 2017/12
Experimental Method:
x-ray diffraction
Resolution: 2.09  Å
Source Organism:
Similar Structures:
Biological Unit for 4TY7: monomeric; determined by author and by software (PISA)
Molecular Components in 4TY7
Label Count Molecule
Protein (1 molecule)
Coagulation Factor XI(Gene symbol: F11)
Molecule annotation
Chemicals (10 molecules)
* Click molecule labels to explore molecular sequence information.

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