2RA0

X-ray Structure of FXa in complex with 7-fluoroindazole

Summary for 2RA0

• Entry DOI: 10.2210/pdb2ra0/pdb
• Descriptor: Coagulation factor X, 1-(3-amino-1,2-benzisoxazol-5-yl)-6-(4-{2-[(dimethylamino)methyl]-1H-imidazol-1-yl}-2-fluorophenyl)-7-fluoro-1H-indazole-3-carboxamide, ... (4 entities in total)
• Functional Keywords: serine protease, blood coagulation, calcium, cleavage on pair of basic residues, egf-like domain, gamma-carboxyglutamic acid, glycoprotein, hydrolase, hydroxylation, polymorphism, zymogen
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P00742 P00742
• Total number of polymer chains: 2
• Total formula weight: 32421.64

Authors

Abad, M.C. (deposition date: 2007-09-14, release date: 2008-01-29, Last modification date: 2024-10-30)

Primary citation

Lee, Y.K.,Parks, D.J.,Lu, T.,Thieu, T.V.,Markotan, T.,Pan, W.,McComsey, D.F.,Milkiewicz, K.L.,Crysler, C.S.,Ninan, N.,Abad, M.C.,Giardino, E.C.,Maryanoff, B.E.,Damiano, B.P.,Player, M.R.
7-fluoroindazoles as potent and selective inhibitors of factor xa.
J.Med.Chem., 51:282-297, 2008

PubMed Abstract: 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.

PubMed: 18159923
DOI: 10.1021/jm701217r

Experimental method

X-RAY DIFFRACTION (2.3 Å)