2ra0
|
X-ray Structure of FXa in complex with 7-fluoroindazole
OverviewOverview
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.
About this StructureAbout this Structure
2RA0 is a Protein complex structure of sequences from Homo sapiens with as ligand. Active as Coagulation factor Xa, with EC number 3.4.21.6 Known structural/functional Site: . Full crystallographic information is available from OCA.
ReferenceReference
7-fluoroindazoles as potent and selective inhibitors of factor xa., Lee YK, Parks DJ, Lu T, Thieu TV, Markotan T, Pan W, McComsey DF, Milkiewicz KL, Crysler CS, Ninan N, Abad MC, Giardino EC, Maryanoff BE, Damiano BP, Player MR, J Med Chem. 2008 Jan 24;51(2):282-97. Epub 2007 Dec 27. PMID:18159923
Page seeded by OCA on Thu Jan 31 10:59:33 2008