2ra0
From Proteopedia
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'''X-ray Structure of FXa in complex with 7-fluoroindazole''' | '''X-ray Structure of FXa in complex with 7-fluoroindazole''' | ||
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[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Abad, M C.]] | [[Category: Abad, M C.]] | ||
| - | [[Category: | + | [[Category: Blood coagulation]] |
| - | [[Category: | + | [[Category: Calcium]] |
| - | [[Category: | + | [[Category: Cleavage on pair of basic residue]] |
| - | [[Category: | + | [[Category: Egf-like domain]] |
| - | [[Category: | + | [[Category: Gamma-carboxyglutamic acid]] |
| - | [[Category: | + | [[Category: Glycoprotein]] |
| - | [[Category: | + | [[Category: Hydrolase]] |
| - | [[Category: | + | [[Category: Hydroxylation]] |
| - | [[Category: | + | [[Category: Polymorphism]] |
| - | [[Category: | + | [[Category: Serine protease]] |
| - | [[Category: | + | [[Category: Zymogen]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 16:30:42 2008'' | |
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Revision as of 13:30, 4 May 2008
X-ray Structure of FXa in complex with 7-fluoroindazole
Contents |
Overview
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.
Disease
Known disease associated with this structure: Factor X deficiency OMIM:[227600]
About this Structure
2RA0 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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 Sun May 4 16:30:42 2008
