2RA0: X-Ray Structure Of Fxa In Complex With 7-Fluoroindazole

We have developed a novel series of potent and selective factor Xa inhibitors that employ a key 7-fluoroindazolyl moiety. The 7-fluoro group on the indazole scaffold replaces the carbonyl group of an amide that is found in previously reported factor Xa inhibitors. The structure of a factor Xa cocrystal containing 7-fluoroindazole 51a showed the 7-fluoro atom hydrogen-bonding with the N-H of Gly216 (2.9 A) in the peptide backbone. Thus, the 7-fluoroindazolyl moiety not only occupied the same space as the carbonyl group of an amide found in prior factor Xa inhibitors but also maintained a hydrogen bond interaction with the protein's beta-sheet domain. The structure-activity relationship for this series was consistent with this finding, as the factor Xa inhibitory potencies were about 60-fold greater (DeltaDelta G approximately 2.4 kcal/mol) for the 7-fluoroindazoles 25a and 25c versus the corresponding indazoles 25b and 25d. Highly convergent synthesis of these factor Xa inhibitors is also described.
PDB ID: 2RA0Download
MMDB ID: 62111
PDB Deposition Date: 2007/9/14
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 2.3  Å
Source Organism:
Similar Structures:
Biological Unit for 2RA0: dimeric; determined by author and by software (PISA)
Molecular Components in 2RA0
Label Count Molecule
Proteins (2 molecules)
Coagulation Factor X(Gene symbol: F10)
Molecule annotation
Coagulation Factor X(Gene symbol: F10)
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

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