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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}
}
  • Doubly [SiMe{sub 2}]-bridged metallocenes (1,2-SiMe{sub 2}){sub 2}{l{underscore}brace}{eta}{sup 5}-C{sub 5}H{sub 2}-4-R{r{underscore}brace}{l{underscore}brace}{eta}{sup 5}-C{sub 5}H-3,5-(CHMe{sub 2}){sup 2}{r{underscore}brace}ZrCl{sub 2} (R = H (1a), CHMe{sub 2} (1b), SiMe{sub 3} (1c), CHMe(CMe{sub 3}) (1d), (+)-menthyl (1e)), when activated by methylaluminoxane (MAO), catalyze propylene polymerization with high activities. The preparations and X-ray structures of the dilithio salt of an enantiopure, doubly silylene-bridged bis(cyclopentadienyl)ligand, Li{sub 2}[(1,2-Me{sub 2}Si){sub 2}-{l{underscore}brace}C{sub 5}H{sub 2}-4-(1R,2S,5R-menthyl){r{underscore}brace}{l{underscore}brace}(C{sub 5}H-3,5-(CHMe{sub 2}){sub 2}){r{underscore}brace}]{center{underscore}dot}3THF, as well as the corresponding zircononcene dichloride, [(1,2-Me{sub 2}Si){sub 2}{l{underscore}brace}{eta}{sup 5}-C{sub 5}H{sub 2}-4-(1R,2S,5R-menthyl){r{underscore}brace}{l{underscore}brace}{eta}{sup 5}-C{sub 5}H-3,5-(CHMe{sub 2}){sub 2}{r{underscore}brace}]ZrCl{sub 2}(1e), are reported. The C{sub s}-symmetric systems 1a-c are highly regiospecific and syndiospecific (> 99.5%) in neat propylene.more » At lower propylene concentrations, polymers with lower molecular weights and tacticity (mostly m-type stereoerrors) are obtained. The microstructures of polymers produced under differing reaction conditions are consistent with stereocontrol dominated by a site epimerization process, an inversion of configuration at zirconium resulting from the polymer chain swinging from one side of the metallocene wedge to the other without monomer insertion. The relative importance of chain epimerization (at the {beta} carbon) has been established by parallel polymerization of 2-d{sub 1}-propylene and d{sub 0}-propylene with 1b/MAO at low propylene concentrations. The C{sub 1}-symmetric systems 1d,e/MAO display an unusual dependence of stereospecificity on propylene concentration, switching from isospecific to syndiospecific with increasing propylene pressure, consistent with a competitive unimolecular site epimerization process and a bimolecular chain propagation. The microstructures of the polypropylenes produced by 1d/MAO and 1e/MAO with [r] {approx} 50% resemble the hemiisotactic microstructure produced by Me{sub 2}C({eta}{sup 5}-C{sub 5}H{sub 3}-3-Me)({eta}{sup 5}-C{sub 13}H{sub 8})ZrCl{sub 2} (2b)/MAO. Contrastingly, the hemiisotactic polypropylene microstructure obtained with 2b/MAO is found to be maintained at all propylene concentrations examined.« less
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  • Blood coagulation can be initiated when factor VII(a) binds to its cofactor tissue factor. This factor VIIa/tissue factor complex proteolytically activates factors IX and X, which eventually leads to the formation of a fibrin clot. Plasma contains a lipoprotein-associated coagulation inhibitor (LACI) which inhibits factor Xa directly and, in a Xa-dependent manner, also inhibits the factor VIIa/tissue factor complex. Here the authors report the cloning of the human LACI gene and the elucidation of its intron-exon organization. The LACI gene, which spans about 70 kb, consists of nine exons separated by eight introns. As has been found for other Kunitz-typemore » protease inhibitors, the domain structure of human LACI is reflected in the intron-exon organization of the gene. The 5{prime} terminus of the LACI mRNA has been determined by primer extension and S1 nuclease mapping. The putative promoter was examined and found to contain two consensus sequences for AP-1 binding and one for NF-1 binding, but no TATA consensus promoter element.« less
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  • No abstract prepared.