7-fluoroindazoles as potent and selective inhibitors of factor Xa
| Autor: | Bruce P. Damiano, Tho V Thieu, Thomas P. Markotan, Tianbao Lu, Yu-Kai Lee, Karen L. Milkiewicz, Nisha S. Ninan, David F. McComsey, Daniel J. Parks, Mark R. Player, Bruce E. Maryanoff, Wenxi Pan, Edward C. Giardino, Marta C. Abad, Carl Crysler |
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| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Cell Membrane Permeability Indazoles Serine Proteinase Inhibitors medicine.drug_mechanism_of_action Stereochemistry Protein Conformation Factor Xa Inhibitor Convergent synthesis In Vitro Techniques Crystallography X-Ray Chemical synthesis chemistry.chemical_compound Structure-Activity Relationship Amide Drug Discovery medicine Moiety Structure–activity relationship Humans Indazole Hydrogen bond Hydrogen Bonding chemistry Factor Xa Microsomes Liver Molecular Medicine Thermodynamics Caco-2 Cells Factor Xa Inhibitors |
| Zdroj: | Journal of medicinal chemistry. 51(2) |
| ISSN: | 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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