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Title: SAR and X-ray Structures of Enantiopure 1,2-cis-(1R,2S)-cyclopentyldiamine and Cyclohexyldiamine Derivativies as Inhibitors of Coagulation Factor Xa

Abstract

In the search of Factor Xa (FXa) inhibitors structurally different from the pyrazole-based series, we identified a viable series of enantiopure cis-(1R,2S)-cycloalkyldiamine derivatives as potent and selective inhibitors of FXa. Among them, cyclohexyldiamide 7 and cyclopentyldiamide 9 were the most potent neutral compounds, and had good anticoagulant activity comparable to the pyrazole-based analogs. Crystal structures of 7-FXa and 9-FXa illustrate binding similarities and differences between the five- and the six-membered core systems, and provide rationales for the observed SAR of P1 and linker moieties.

Authors:
; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
930032
Report Number(s):
BNL-80648-2008-JA
TRN: US200822%%1267
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: BioOrganic and Medicinal Chemistry Letters; Journal Volume: 17
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; ANTICOAGULANTS; CRYSTAL STRUCTURE; ENZYMES; STRUCTURAL CHEMICAL ANALYSIS; X-RAY DIFFRACTION; national synchrotron light source

Citation Formats

Qiao,J., Chang, C., Cheney, D., Morin, D., Wang, P., King, G., Wang, S., Rendina, T., Luettgen, A., and et al. SAR and X-ray Structures of Enantiopure 1,2-cis-(1R,2S)-cyclopentyldiamine and Cyclohexyldiamine Derivativies as Inhibitors of Coagulation Factor Xa. United States: N. p., 2007. Web. doi:10.1016/j.bmcl.2007.06.029.
Qiao,J., Chang, C., Cheney, D., Morin, D., Wang, P., King, G., Wang, S., Rendina, T., Luettgen, A., & et al. SAR and X-ray Structures of Enantiopure 1,2-cis-(1R,2S)-cyclopentyldiamine and Cyclohexyldiamine Derivativies as Inhibitors of Coagulation Factor Xa. United States. doi:10.1016/j.bmcl.2007.06.029.
Qiao,J., Chang, C., Cheney, D., Morin, D., Wang, P., King, G., Wang, S., Rendina, T., Luettgen, A., and et al. Mon . "SAR and X-ray Structures of Enantiopure 1,2-cis-(1R,2S)-cyclopentyldiamine and Cyclohexyldiamine Derivativies as Inhibitors of Coagulation Factor Xa". United States. doi:10.1016/j.bmcl.2007.06.029.
@article{osti_930032,
title = {SAR and X-ray Structures of Enantiopure 1,2-cis-(1R,2S)-cyclopentyldiamine and Cyclohexyldiamine Derivativies as Inhibitors of Coagulation Factor Xa},
author = {Qiao,J. and Chang, C. and Cheney, D. and Morin, D. and Wang, P. and King, G. and Wang, S. and Rendina, T. and Luettgen, A. and et al.},
abstractNote = {In the search of Factor Xa (FXa) inhibitors structurally different from the pyrazole-based series, we identified a viable series of enantiopure cis-(1R,2S)-cycloalkyldiamine derivatives as potent and selective inhibitors of FXa. Among them, cyclohexyldiamide 7 and cyclopentyldiamide 9 were the most potent neutral compounds, and had good anticoagulant activity comparable to the pyrazole-based analogs. Crystal structures of 7-FXa and 9-FXa illustrate binding similarities and differences between the five- and the six-membered core systems, and provide rationales for the observed SAR of P1 and linker moieties.},
doi = {10.1016/j.bmcl.2007.06.029},
journal = {BioOrganic and Medicinal Chemistry Letters},
number = ,
volume = 17,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}